Vanilloid receptor ligands and their use in treatments

ABSTRACT

Compounds having the general structure  
                 
and compositions containing them, for the treatment of acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burns, allergic skin reactions, pruritus, vitiligo, general gastrointestinal disorders, gastric ulceration, duodenal ulcers, diarrhea, gastric lesions induced by necrotising agents, hair growth, vasomotor or allergic rhinitis, bronchial disorders or bladder disorders.

This application claims the benefit of U.S. Provisional Application No.60/538,772, filed Jan. 23, 2004, which is hereby incorporated byreference.

BACKGROUND

The vanilloid receptor 1 (VR1) is the molecular target of capsaicin, theactive ingredient in hot peppers. Julius et al. reported the molecularcloning of VR1 (Caterina et al., 1997). VR1 is a non-selective cationchannel which is activated or sensitized by a series of differentstimuli including capsaicin and resiniferatoxin (exogenous activators),heat & acid stimulation and products of lipid bilayer metabolism,anandamide (Premkumar et al., 2000, Szabo et al., 2000, Gauldie et al.,2001, Olah et al., 2001) and lipoxygenase metabolites (Hwang et al.,2000). VR1 is highly expressed in primary sensory neurons (Caterina etal., 1997) in rats, mice and humans (Onozawa et al., 2000, Mezey et al.,2000, Helliwell et al., 1998, Cortright et al., 2001). These sensoryneurons innervate many visceral organs including the dermis, bones,bladder, gastrointestinal tract and lungs; VR1 is also expressed inother neuronal and non-neuronal tissues including but not limited to,CNS nuclei, kidney, stomach and T-cells (Nozawa et al., 2001, Yiangou etal., 2001, Birder et al., 2001). Presumably expression in these variouscells and organs may contribute to their basic properties such ascellular signaling and cell division.

Prior to the molecular cloning of VR1, experimentation with capsaicinindicated the presence of a capsaicin sensitive receptor, which couldincrease the activity of sensory neurons in humans, rats and mice(Holzer, 1991; Dray, 1992, Szallasi and Blumberg 1996, 1999). The resultof acute activation by capsaicin in humans was pain at injection siteand in other species increased behavioral sensitivity to sensory stimuli(Szallasi and Blumberg, 1999). Capsaicin application to the skin inhumans causes a painful reaction characterized not only by theperception of heat and pain at the site of administration but also by awider area of hyperalgesia and allodynia, two characteristic symptoms ofthe human condition of neuropathic pain (Holzer, 1991). Taken together,it seems likely that increased activity of VR1 plays a significant rolein the establishment and maintenance of pain conditions. Topical orintradermal injection of capsaicin has also been shown to producelocalized vasodilation and edema production (Szallasi and Blumberg 1999,Singh et al., 2001). This evidence indicates that capsaicin through it'sactivation of VR1 can regulate afferent and efferent function of sensorynerves. Sensory nerve involvement in diseases could therefore bemodified by molecules, which affect the function of the vanilloidreceptor to increase or decrease the activity of sensory nerves.

VR1 gene knockout mice have been shown to reduce sensory sensitivity tothermal and acid stimuli (Caterina et al., 2000)). This supports theconcept that VR1 contributes not only to generation of pain responses(i.e. via thermal, acid or capsaicin stimuli) but also to themaintenance of basal activity of sensory nerves. This evidence agreeswith studies demonstrating capsaicin sensitive nerve involvement indisease. Primary sensory nerves in humans and other species can be madeinactive by continued capsaicin stimulation. This paradigm causesreceptor activation induced desensitization of the primary sensorynerve—such reduction in sensory nerve activity in vivo makes subjectsless sensitive to subsequent painful stimuli. In this regard bothcapsaicin and resinferatoxin (exogenous activators of VR1), producedesensitization and they have been used for many proof of conceptstudies in in vivo models of disease (Holzer, 1991, Dray 1992, Szallasiand Blumberg 1999).

BIBLIOGRAPHY

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SUMMARY

The present invention comprises a new class of compounds useful in thetreatment of diseases, such as vanilloid-receptor-mediated diseases andother maladies, such as inflammatory or neuropathic pain and diseasesinvolving sensory nerve function such as asthma, rheumatoid arthritis,osteoarthritis, inflammatory bowel disorders, urinary incontinence,migraine and psoriasis. In particular, the compounds of the inventionare useful for the treatment of acute, inflammatory and neuropathicpain, dental pain, general headache, migraine, cluster headache,mixed-vascular and non-vascular syndromes, tension headache, generalinflammation, arthritis, rheumatic diseases, osteoarthritis,inflammatory bowel disorders, inflammatory eye disorders, inflammatoryor unstable bladder disorders, psoriasis, skin complaints withinflammatory components, chronic inflammatory conditions, inflammatorypain and associated hyperalgesia and allodynia, neuropathic pain andassociated hyperalgesia and allodynia, diabetic neuropathy pain,causalgia, sympathetically maintained pain, deafferentation syndromes,asthma, epithelial tissue damage or dysfunction, herpes simplex,disturbances of visceral motility at respiratory, genitourinary,gastrointestinal or vascular regions, wounds, burns, allergic skinreactions, pruritus, vitiligo, general gastrointestinal disorders,gastric ulceration, duodenal ulcers, diarrhea, gastric lesions inducedby necrotising agents, hair growth, vasomotor or allergic rhinitis,bronchial disorders or bladder disorders. Accordingly, the inventionalso comprises pharmaceutical compositions comprising the compounds,methods for the treatment of vanilloid-receptor-mediated diseases, suchas inflammatory or neuropathic pain, asthma, rheumatoid arthritis,osteoarthritis, inflammatory bowel disorders, urinary incontinence,migraine and psoriasis diseases, using the compounds and compositions ofthe invention, and intermediates and processes useful for thepreparation of the compounds of the invention.

The compounds of the invention are represented by the following generalstructure:

a pharmaceutically acceptable salt thereof, wherein R¹, R², R³, q, r, s,P, X and Y are defined below.

The foregoing merely summarizes certain aspects of the invention and isnot intended, nor should it be construed, as limiting the invention inany way. All patents, patent applications and other publications recitedherein are hereby incorporated by reference in their entirety.

DETAILED DESCRIPTION

Published patent application WO 03068749 is incorporated by reference inits entirety.

One aspect of the current invention relates to compounds having thegeneral structure:

or a pharmaceutically acceptable salt or solvate thereof, wherein,

-   -   P is selected from phenyl, heteroaryl or heterocyclyl;    -   R¹ and R² are independently selected from halo, alkyl, alkoxy,        cycloalkyl, aralkyl, aralkoxy, cycloalkylalkyl,        cycloalkylalkoxy, —CN, —NO₂, —OH, ═O, —OCF₃, —CF₃, NR⁴R⁵,        —S(O)_(m)R⁶, —S(O)₂NR⁴R⁵, —OS(O)₂R⁶, —OS(O)₂CF₃, —O(CH₂)NR⁴R⁵′,        —C(O)CF₃, —C(O)alkyl, —C(O)cycloalkyl, —C(O)aralkyl, —C(O)Ar,        —C(O)(CH₂)_(n)OR⁶, C(O)(CH₂)_(n)NR⁴R⁵, —C(O)alkoxy, —C(O)NR⁴R⁵,        —(CH₂)_(n)C(O)alkoxy, (CH₂)_(n)OC(O)R⁶, —O(CH₂)_(n)OR⁶,        —(CH₂)_(n)OR⁶, —(CH₂)_(n)NR⁴R⁵ (CH₂)_(n)C(O)NR⁴R⁵,        —(CH₂)_(n)N(R⁴)C(O)R⁶, —(CH₂)_(n)S(O)₂NR⁴R⁵,        (CH₂)_(n)N(R⁴)S(O)₂R⁶, -ZAr, —(CH₂)_(n)S(O)₂R⁶,        —(OCH₂)_(n)S(O)₂R⁶, N(R⁴)S(O)₂R⁶, —N(R⁴)C(O)R⁶,        —(CH₂)_(n)N(R⁴)S(O)₂R⁶, —(CH₂)_(n)N(R⁴)C(O)R⁶ or        —(CH₂)_(n)C(O)alkyl;    -   R³ is selected from alkyl, alkoxy, —CF₃, halo, —O(CH₂)nOR⁶,        —O(CH₂)_(n)NR⁴R⁵, phenyl, cyclohexyl, benzo[1,3]dioxolyl,        morpholinyl, pyridyl, pyrimidinyl, pyrazinyl, piperazinyl,        piperidinyl, pyridizinyl, thienyl, furyl, pyrazolyl, pyrrolyl,        triazolyl, indanyl, imidazolyl, oxazolyl, thiazolyl,        oxadiazolyl, isothiazolyl, isoxazolyl or thiadiazolyl; wherein        said alkyl, alkoxy, phenyl, cyclohexyl, benzo[1,3]dioxolyl,        morpholinyl, pyridyl, pyrimidinyl, pyrazinyl, piperazinyl,        piperidinyl, pyridizinyl, thienyl, furyl, pyrazolyl, pyrrolyl,        triazolyl, indanyl, imidazolyl, oxazolyl, thiazolyl,        oxediazolyl, isothiazolyl, isoxazolyl and thiadiazolyl groups        may be optionally substituted by one or more groups, which may        be the same or different, selected from R²;    -   R⁴ and R⁵ may be the same or different and represent —H or alkyl        or R⁴ and R⁵ together with the nitrogen atom to which they are        attached form a heterocyclic ring;    -   R⁶ is —H, alkyl or aryl;    -   R⁷ is —H, alkyl or aryl;    -   R⁸ is selected from H, alkyl, hydroxyalkyl, cycloalkyl, aralkyl,        alkoxyalkyl, cycloalkylalkyl, heterocyclylalkyl, —S(O)_(m)R⁶,        —C(O)CF₃, —C(O)alkyl, —C(O)cycloalkyl, —C(O)aralkyl, —C(O)Ar,        —C(O)(CH₂)_(n)OR⁶, —C(O)(CH₂)_(n)NR⁴R⁵, C(O)alkoxy, —C(O)NR⁴R⁵,        —(CH₂)_(n)C(O)alkoxy, —(CH₂)_(n)OC(O)R⁶, —(CH₂)_(n)OR⁶,        —(CH₂)_(n)NR⁴R⁵, —(CH₂)_(n)C(O)NR⁴R⁵, —(CH₂)_(n)N(R⁴)C(O)R⁶,        —(CH₂)_(n)S(O)₂NR⁴R⁵, —(CH₂)_(n)N(R⁴)S(O)₂R⁶, —(CH₂)_(n)S(O)₂R⁶,        —(CH₂)_(n)N(R⁴)S(O)₂R⁶, —(CH₂)_(n)N(R⁴)C(O)R⁶ or        —(CH₂)_(n)C(O)alkyl; or where X is NR⁸ and Y is C(R⁹)₂, R⁸ may        combine with R¹ to form a benzoquinuclidine group;    -   R⁹ is H or R¹;    -   Ar is aryl or heteroaryl, each of which may be optionally        substituted by R²;    -   Z is a bond, O, S, NR⁷ or CH₂;    -   m is 0, 1 or 2;    -   n is an integer value from 1 to 6;    -   q and r are independently selected from 0, 1, 2 or 3;    -   s is 0, 1, 2 or 3; and

X and Y are selected from the following combinations: X Y N CR⁹ NR⁸C(R⁹)₂ CR⁹ N C(R⁹)₂ NR⁸with the proviso that said compound of formula (I) is not a compoundselected from:

-   N-{3-[(N,N-dimethylamino)methyl]-1,2,3,4-tetrahydro-7-guinolinyl}-4    biphenylcarboxamide;-   N-{3-[(N,N-dimethylamino)methyl]-1-formyl-1,2,3,4-tetrahydro-7-quinolinyl}-4-biphenylcarboxamide;-   N-{1-acetyl-3-[(N,N-dimethylamino)methyl]-1,2,3,4-tetrahydro-7-quinolinyl}-4    biphenylcarboxamide;-   N-{3-[(N,N-dimethylamino)methyl]-1-methylsulfonyl-1,2,3,4-tetrahydro-7    quinolinyl}-4-biphenylcarboxamide;-   5-amino-N-isoquinolin-5-yl-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3    carboxamide;-   5-methyl-N-quinolin-8-yl-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3    carboxamide;-   5-methyl-N-quinolin-7-yl-1-[3-trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide;-   5-methyl-N-quinolin-3-yl-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide;-   N-isoquinolin-5-yl-5-methyl-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide;-   5-methyl-N-quinolin-5-yl-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide;-   1-(3-chlorophenyl)-N-isoquinolin-5-yl-5-methyl-1H-pyrazole-3-carboxamide;-   N-isoquinolin-5-yl-1-(3-methoxyphenyl)-5-methyl-1H-pyrazole-3-carboxamide;-   1-(3-fluorophenyl)-N-isoquinolin-5-yl-5-methyl-1H-pyrazole-3-carboxamide;-   1-(2-chloro-5-trifluoromethylphenyl)-N-isoquinolin-5-yl-5-methyl-1H-pyrazole-3    carboxamide;-   5-methyl-N-(3-methylisoquinolin-5-yl)-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide;    and-   5-methyl-N-(1,2,3,4-tetrahydroisoquinolin-5-yl)-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide.

In another embodiment, the compounds of the present invention arerepresented by the formula

or a pharmaceutically acceptable salt or solvate thereof, wherein,

-   -   J is ═O, ═S, ═CHNO₂, ═N—CN, ═CHSO₂R^(b), ═NSO₂R^(b) or ═NHR^(b);    -   P is selected from phenyl, heteroaryl or heterocyclyl;    -   R¹ and R² are independently selected from halo, alkyl, alkoxy,        cycloalkyl, aralkyl, aralkoxy, cycloalkylalkyl,        cycloalkylalkoxy, —CN, —NO₂, —OH, ═O, —OCF₃, —CF₃, NR⁴R⁵,        —S(O)_(m)R⁶, —S(O)₂NR⁴R⁵, —OS(O)₂R⁶, —OS(O)₂CF₃,        —O(CH₂)_(n)NR⁴R⁵, —C(O)CF₃, —C(O)H, —C(O)alkyl, —C(O)cycloalkyl,        —C(O)aralkyl, —C(O)Ar, —C(O)(CH₂)_(n)OR⁶, C(O)(CH₂)_(n)NR⁴R⁵,        —C(O)alkoxy, —C(O)NR⁴R⁵, —(CH₂)_(n)C(O)alkoxy, (CH₂)_(n)OC(O)R⁶,        —O(CH₂)_(n)OR⁶, —O(CH₂)_(n)NR⁴R⁵—NH(CH₂)_(n)NR⁴R⁵,        —(CH₂)_(n)OR⁶, —(CH₂)_(n)NR⁴R⁵, —(CH₂)_(n)C(O)NR⁴R⁵,        —(CH₂)_(n)N(R⁴)C(O)R⁶, —(CH₂)_(n)S(O)₂NR⁴R⁵,        (CH₂)_(n)N(R⁴)S(O)₂R⁶, -ZAr, —(CH₂)_(n)S(O)₂R⁶,        —(OCH₂)_(n)S(O)₂R⁶, N(R⁴)S(O)₂R⁶, —N(R⁴)C(O)R⁶,        —(CH₂)_(n)N(R⁴)S(O)₂R⁶, —(CH₂)_(n)N(R⁴)C(O)R⁶ or        —(CH₂)_(n)C(O)alkyl;    -   R³ is selected from alkyl, alkoxy, —CF₃, halo, —O(CH₂)_(n)OR⁶,        —O(CH₂)_(n)NR⁴R⁵, phenyl, —Ophenyl, —NHphenyl, —N(alkyl)phenyl,        —Oheteroaryl, —NHheteroaryl, —N(alkyl)heteroaryl, cyclohexyl,        benzo[1,3]dioxolyl, morpholinyl, pyridyl, pyrimidinyl,        pyrazinyl, piperazinyl, piperidinyl, pyridizinyl, thienyl,        furyl, pyrazolyl, pyrrolyl, triazolyl, indanyl, imidazolyl,        oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl or        thiadiazolyl; wherein said alkyl, alkoxy, phenyl, cyclohexyl,        benzo[1,3]dioxolyl, morpholinyl, pyridyl, pyrimidinyl,        pyrazinyl, piperazinyl, piperidinyl, pyridizinyl, thienyl,        furyl, pyrazolyl, pyrrolyl, triazolyl, indanyl, imidazolyl,        oxazolyl, thiazolyl, oxediazolyl, isothiazolyl, isoxazolyl and        thiadiazolyl groups may be optionally substituted by one or more        groups, which may be the same or different, selected from R²;    -   R⁴ and R⁵ may be the same or different and represent —H or alkyl        or R⁴ and R⁵ together with the nitrogen atom to which they are        attached form a heterocyclic ring;    -   R⁶ is —H, alkyl or aryl;    -   R⁷ is —H, alkyl or aryl;    -   R⁸ is selected from H, alkyl, hydroxyalkyl, cycloalkyl, aralkyl,        alkoxyalkyl, cycloalkylalkyl, heterocyclylalkyl, —S(O)_(m)R⁶,        —C(O)CF₃, —C(O)alkyl, —C(O)cycloalkyl, —C(O)aralkyl, —C(O)Ar,        —C(O)(CH₂)_(n)OR⁶, —C(O)(CH₂)_(n)NR⁴R⁵, C(O)alkoxy, —C(O)NR⁴R⁵,        —(CH₂)_(n)C(O)alkoxy, —(CH₂)_(n)OC(O)R⁶, —(CH₂)_(n)OR⁶,        —(CH₂)NR⁴R⁵, —(CH₂)_(n)C(O)NR⁴R⁵, —(CH₂)_(n)N(R⁴)C(O)R⁶,        —(CH₂)_(n)S(O)₂NR⁴R⁵, —(CH₂)_(n)N(R⁴)S(O)₂R⁶, —(CH₂)_(n)S(O)₂R⁶,        —(CH₂)_(n)N(R⁴)S(O)₂R⁶, —(CH₂)_(n)N(R⁴)C(O)R⁶ or        —(CH₂)_(n)C(O)alkyl; or where X is NR⁸ and Y is C(R⁹)₂, R⁸ may        combine with R¹ to form a benzoquinuclidine group;    -   R⁹ is H or R¹;    -   Ar is aryl or heteroaryl, each of which may be optionally        substituted by R²;    -   Z is a bond, O, S, NR⁷ or CH₂;    -   m is 0, 1 or 2;    -   n is an integer value from 1 to 6;    -   q and r are independently selected from 0, 1, 2 or 3;    -   s is 0, 1, 2 or 3; and

X and Y are selected from the following combinations: X Y N CR⁹ NR⁸C(R⁹)₂ CR⁹ N C(R⁹)₂ NR⁸with the proviso that said compound of formula (I) is not a compoundselected from:

-   N-{3-[(N,N-Dimethylamino)methyl]-1,2,3,4-tetrahydro-7-guinolinyl}-4    biphenylcarboxamide;-   N-{3-[(N,N-Dimethylamino)methyl]-1-formyl-1,2,3,4-tetrahydro-7-quinolinyl}-4-biphenylcarboxamide;-   N-{1-Acetyl-3-[(N,N-dimethylamino)methyl]-1,2,3,4-tetrahydro-7-quinolinyl}-4    biphenylcarboxamide;-   N-{3-[(N,N-Dimethylamino)methyl]-1-methylsulfonyl-1,2,3,4-tetrahydro-7    quinolinyl}-4-biphenylcarboxamide;-   5-amino-N-isoquinolin-5-yl-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3    carboxamide;-   5-methyl-N-quinolin-8-yl-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3    carboxamide;-   5-methyl-N-quinolin-7-yl-1-[3-trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide;-   5-methyl-N-quinolin-3-yl-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide;-   N-isoquinolin-5-yl-5-methyl-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide;-   5-methyl-N-quinolin-5-yl-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide;-   1-(3-chlorophenyl)-N-isoquinolin-5-yl-5-methyl-1H-pyrazole-3-carboxamide;-   N-isoquinolin-5-yl-1-(3-methoxyphenyl)-5-methyl-1H-pyrazole-3-carboxamide;-   1-(3-fluorophenyl)-N-isoquinolin-5-yl-5-methyl-1H-pyrazole-3-carboxamide;-   1-(2-chloro-5-trifluoromethylphenyl)-N-isoquinolin-5-yl-5-methyl-1H-pyrazole-3    carboxamide;-   5-methyl-N-(3-methylisoquinolin-5-yl)-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide;    and-   5-methyl-N-(1,2,3,4-tetrahydroisoquinolin-5-yl)-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide.

In another embodiment, the compounds of the present invention arerepresented by the formula

or a pharmaceutically acceptable salt or solvate thereof, wherein,

-   -   P is selected from phenyl, heteroaryl or heterocyclyl;    -   R¹ and R² are independently selected from halo, alkyl, alkoxy,        cycloalkyl, aralkyl, aralkoxy, cycloalkylalkyl,        cycloalkylalkoxy, —CN, —NO₂, —OH, ═O, —OCF₃, —CF₃, NR⁴R⁵,        —S(O)_(m)R⁶, —S(O)₂NR⁴R⁵, —OS(O)₂R⁶, —OS(O)₂CF₃,        —O(CH₂)_(n)NR⁴R⁵, —C(O)CF₃, —C(O)alkyl, —C(O)cycloalkyl,        —C(O)aralkyl, —C(O)Ar, —C(O)(CH₂)_(n)OR⁶, C(O)(CH₂)_(n)NR⁴R⁵,        —C(O)alkoxy, —C(O)NR⁴R⁵, —(CH₂)_(n)C(O)alkoxy, (CH₂)_(n)OC(O)R⁶,        —O(CH₂)_(n)OR⁶, —(CH₂)_(n)OR⁶, —(CH₂)_(n)NR⁴R⁵,        (CH₂)_(n)C(O)NR⁴R⁵, —(CH₂)_(n)N(R⁴)C(O)R⁶, —(CH₂)_(n)S(O)₂NR⁴R⁵,        (CH₂)_(n)N(R⁴)S(O)₂R⁶, -ZAr, —(CH₂)_(n)S(O)₂R⁶,        (OCH₂)_(n)S(O)₂R⁶, N(R⁴)S(O)₂R⁶, —N(R⁴)C(O)R⁶,        —(CH₂)_(n)N(R⁴)S(O)₂R⁶, —(CH₂)_(n)N(R⁴)C(O)R⁶ or        (CH₂)_(n)C(O)alkyl;    -   R³ is selected from alkyl, —CF₃, halo, phenyl, cyclohexyl,        benzo[1,3]dioxolyl morpholinyl, pyridyl, pyrimidinyl, pyrazinyl,        piperazinyl piperidinyl, pyridizinyl, thienyl, furyl, pyrazolyl,        pyrrolyl, triazolyl, indanyl, imidazolyl, oxazolyl, thiazolyl,        oxadiazolyl, isothiazolyl, isoxazolyl or thiadiazolyl; wherein        said alkyl, alkoxy, phenyl, cyclohexyl, benzo[1,3]dioxolyl,        morpholinyl, pyridyl, pyrimidinyl, pyrazinyl, piperazinyl,        piperidinyl, pyridizinyl, thienyl, furyl, pyrazolyl, pyrrolyl,        triazolyl, indanyl, imidazolyl, oxazolyl, thiazolyl,        oxadiazolyl, isothiazolyl, isoxazolyl and thiadiazolyl groups        may be optionally substituted by one or more groups, which may        be the same or different, selected from R²;    -   R⁴ and R⁵ may be the same or different and represent —H or alkyl        or R⁴ and R⁵ together with the nitrogen atom to which they are        attached form a heterocyclic ring;    -   R⁶ is H, alkyl or aryl;    -   R⁷ is —H, alkyl or aryl;    -   R⁸ is selected from —H, alkyl, hydroxyalkyl, cycloalkyl,        aralkyl, alkoxyalkyl, cycloalkylalkyl, heterocyclylalkyl,        —S(O)_(m)R⁶, —C(O)CF₃, —C(O)alkyl, C(O)cycloalkyl, —C(O)aralkyl,        —C(O)Ar, —C(O)(CH₂)_(n)OR⁶, —C(O)(CH₂)_(n)NR⁴R⁵, C(O)alkoxy,        —C(O)NR⁴R⁵, —(CH₂)_(n)C(O)alkoxy, —(CH₂)_(n)OC(O)R⁶,        —(CH₂)_(n)OR⁶, (CH₂)_(n)NR⁴R⁵, —(CH₂)_(n)C(O)NR⁴R⁵,        —(CH₂)_(n)N(R⁴)C(O)R⁶, —(CH₂)_(n)S(O)₂NR⁴R⁵,        —(CH₂)_(n)N(R⁴)S(O)₂R⁶, —(CH₂)_(n)S(O)₂R⁶,        —(CH₂)_(n)N(R⁴)S(O)₂R⁶, —(CH₂)_(n)N(R⁴)C(O)R⁶ or        —(CH₂)_(n)C(O)alkyl; or where X is NR⁸ and Y is C(R⁹)₂, R⁸ may        combine with R¹ to form a benzoquinuclidine group;    -   R⁹ is —H or R¹;    -   Ar is aryl or heteroaryl, each of which may be optionally        substituted by R²;    -   Z is a bond, O, S, NR⁷ or CH₂;    -   m is 0, 1 or 2;    -   n is an integer value from 1 to 6;    -   q and r are independently selected from 0, 1, 2 or 3;    -   s is 0, 1, 2 or 3; and    -   X is C(R⁹)₂ and Y is NR⁸ or X is NR⁸ and Y is C(R⁹)2;    -   with the proviso that said compound is not a compound selected        from:

-   N-{3-[(N,N-Dimethylamino)methyl]-1,2,3,4-tetrahydro-7-quinolinyl}-4    biphenylcarboxamide;

-   N-{3-[(N,N-Dimethylamino)methyl]-1-formyl-1,2,3,4-tetrahydro-7-quinolinyl}-4    biphenylcarboxamide;

-   N-{1-Acetyl-3-[(N,N-dimethylamino)methyl]-1,2,3,4-tetrahydro-7-quinolinyl}-4    biphenylcarboxamide;

-   N-{3-[(N,N-Dimethylamino)methyl]-1-methylsulfonyl-1,2,3,4-tetrahydro-7-quinolinyl}-4-biphenylcarboxamide;    and

-   5-methyl-N-(1,2,3,4-tetrahydroisoquinolin-5-yl)-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide.

In another embodiment, the compounds of the present invention arerepresented by the formula

or a pharmaceutically acceptable salt or solvate thereof, wherein,

-   -   P is selected from phenyl, heteroaryl or heterocyclyl;    -   R¹ and R² are independently selected from halo, alkyl, alkoxy,        cycloalkyl, aralkyl, aralkoxy, cycloalkylalkyl,        cycloalkylalkoxy, —CN, —NO₂, —OH, —OCF₃, —CF₃, —NR⁴R⁵,        —S(O)_(m)R⁶, —S(O)₂NR⁴R⁵, —OS(O)₂R⁶, —OS(O)₂CF₃,        —O(CH₂)_(n)NR⁴R⁵, —C(O)CF₃, —C(O)alkyl, —C(O)cycloalkyl,        —C(O)aralkyl, —C(O)Ar, —C(O)(CH₂)_(n)OR⁶, —C(O)(CH₂)_(n)NR⁴R⁵,        —C(O)alkoxy, —C(O)NR⁴R⁵, —(CH₂)_(n)C(O)alkoxy, (CH₂)_(n)OC(O)R⁶,        —(CH₂)_(n)OR⁶, —(CH₂)_(n)NR⁴R⁵, —(CH₂)_(n)C(O)NR⁴R⁵,        —(CH₂)_(n)N(R⁴)C(O)R⁶, —(CH₂)_(n)S(O)₂NR⁴R⁵,        —(CH₂)_(n)N(R⁴)S(O)₂R⁶, -ZAr, —(CH₂)_(n)S(O)₂R⁶,        —(OCH₂)_(n)S(O)₂R⁶, —N(R⁴)S(O)₂R⁶, —N(R⁴)C(O)R⁶,        —(CH₂)_(n)N(R⁴)S(O)₂R⁶, —(CH₂)_(n)N(R⁴)C(O)R⁶ or        —(CH₂)_(n)C(O)alkyl;    -   R³ is selected from halo, —CF₃, alkyl, alkoxy, —O(CH₂)_(n)OR⁶,        —O(CH₂)_(n)NR⁴R⁵, phenyl, cyclohexyl, benzo[1,3]dioxolyl,        morpholinyl, pyridyl, pyrimidinyl, pyrazinyl, piperazinyl,        piperidinyl, pyridizinyl, thienyl, furyl, pyrazolyl, pyrrolyl,        triazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl,        isothiazolyl, isoxazolyl or thiadiazolyl; which alkyl, alkoxy,        phenyl, cyclohexyl, benzo[1,3]dioxolyl, morpholinyl, pyridyl,        pyrimidinyl, pyrazinyl, piperazinyl, piperidinyl, pyridizinyl,        thienyl, furyl, pyrazolyl, pyrrolyl, triazolyl, imidazolyl,        oxazolyl, thiazolyl, oxediazolyl, isothiazolyl, isoxazolyl and        thiadiazolyl groups may be optionally substituted by one or more        groups, which may be the same or different, selected from R²;    -   R⁴ and R⁵ may be the same or different and represent H or alkyl        or R⁴ and R⁵ together with the nitrogen atom to which they are        attached form a heterocyclic ring;    -   R⁶ is H, alkyl or aryl;    -   R⁷ is H, alkyl or aryl;    -   Ar is aryl or heteroaryl; each of which may be optionally        substituted by R²;    -   X and Y are selected from CR⁹ and N with the proviso that X and        Y may not be the same;    -   Z is a bond, O, S, NR⁷ or CH₂;    -   m is 0, 1 or 2;    -   n is an integer value from 1 to 6;    -   q and r are independently selected from 0, 1, 2 or 3; and    -   s is 0, 1, or 3;    -   with the proviso that said compound is not a compound selected        from:

-   5-amino-N-isoquinolin-5-yl-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3    carboxamide;

-   5-methyl-N-quinolin-8-yl-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3    carboxamide;

-   5-methyl-N-quinolin-7-yl-1-[3-trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide;

-   5-methyl-N-quinolin-3-yl-1-[3-(trifluoromethyl)phenyl]-1H—    pyrazole-3-carboxamide;

-   N-isoquinolin-5-yl-5-methyl-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3    carboxamide;

-   5-methyl-N-quinolin-5-yl-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3    carboxamide;

-   1-(3-chlorophenyl)-N-isoquinolin-5-yl-5-methyl-1H-pyrazole-3-carboxamide;

-   N-isoquinolin-5-yl-1-(3-methoxyphenyl)-5-methyl-1H-pyrazole-3-carboxamide;

-   1-(3-fuorophenyl)-N-isoquinolin-5-yl-5-methyl-1H-pyrazole-3-carboxamide;

-   1-(2-chloro-5-trifluoromethylphenyl)-N-isoquinolin-5-yl-5-methyl-1H-pyrazole-3    carboxamide;

-   5-methyl-N-(3-methylisoquinolin-5-yl)-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3    carboxamide; and

-   N-[3-[2-(diethylamino)ethyl]-1,2-dihydro-4-methyl-2-oxo-7-quinolinyl]-4-phenyl-1-piperazinecarboxamide.

Another aspect of the invention relates to method for the treatment orprophylaxis of disorders in which antagonism of the VR1 receptor isbeneficial in mammals, which method comprises administering to a mammalin need thereof a therapeutically effective amount of a compoundaccording to any of the above embodiments.

Another aspect of the invention relates to the use of a compoundaccording to any of the above embodiments, in the manufacture of amedicament for the treatment or prophylaxis of disorders in whichantagonism of the Vanillold (VR¹) receptor is beneficial.

Another aspect of the invention relates to a pharmaceutical composition,which comprises a compound according to any of the above embodiments,and a pharmaceutically acceptable carrier or excipient therefor.

Another aspect of the invention relates to a method of treating acute,inflammatory and neuropathic pain, dental pain, general headache,migraine, cluster headache, mixed-vascular and non-vascular syndromes,tension headache, general inflammation, arthritis, rheumatic diseases,osteoarthritis, inflammatory bowel disorders, inflammatory eyedisorders, inflammatory or unstable bladder disorders, psoriasis, skincomplaints with inflammatory components, chronic inflammatoryconditions, inflammatory pain and associated hyperalgesia and allodynia,neuropathic pain and associated hyperalgesia and allodynia, diabeticneuropathy pain, causalgia, sympathetically maintained pain,deafferentation syndromes, asthma, epithelial tissue damage ordysfunction, herpes simplex, disturbances of visceral motility atrespiratory, genitourinary, gastrointestinal or vascular regions,wounds, burns, allergic skin reactions, pruritus, vitiligo, generalgastrointestinal disorders, gastric ulceration, duodenal ulcers,diarrhea, gastric lesions induced by necrotising agents, hair growth,vasomotor or allergic rhinitis, bronchial disorders or bladderdisorders, comprising the step of administering a compound according toany of the above embodiments.

Another aspect of the invention relates to the use of a compoundaccording to any of the above embodiments as a medicament.

Another aspect of the invention relates to the use of a compoundaccording to any of the above embodiments in the manufacture of amedicament for the treatment of acute, inflammatory and neuropathicpain, dental pain, general headache, migraine, cluster headache,mixed-vascular and non-vascular syndromes, tension headache, generalinflammation, arthritis, rheumatic diseases, osteoarthritis,inflammatory bowel disorders, inflammatory eye disorders, inflammatoryor unstable bladder disorders, psoriasis, skin complaints withinflammatory components, chronic inflammatory conditions, inflammatorypain and associated hyperalgesia and allodynia, neuropathic pain andassociated hyperalgesia and allodynia, diabetic neuropathy pain,causalgia, sympathetically maintained pain, deafferentation syndromes,asthma, epithelial tissue damage or dysfunction, herpes simplex,disturbances of visceral motility at respiratory, genitourinary,gastrointestinal or vascular regions, wounds, burns, allergic skinreactions, pruritus, vitiligo, general gastrointestinal disorders,gastric ulceration, duodenal ulcers, diarrhea, gastric lesions inducedby necrotising agents, hair growth, vasomotor or allergic rhinitis,bronchial disorders or bladder disorders.

The compounds of this invention may have in general several asymmetriccenters and are typically depicted in the form of racemic mixtures. Thisinvention is intended to encompass racemic mixtures, partially racemicmixtures and separate enantiomers and diasteromers.

Unless otherwise specified, the following definitions apply to termsfound in the specification and claims:

“C_(α-β)alkyl” means an alkyl group comprising a minimum of α and amaximum of β carbon atoms in a branched, cyclical or linear relationshipor any combination of the three, wherein α and β represent integers. Thealkyl groups described in this section may also contain one or twodouble or triple bonds. Examples of C₁₋₆alkyl include, but are notlimited to the following:

“Benzo group”, alone or in combination, means the divalent radicalC₄H₄═, one representation of which is —CH═CH—CH═CH—, that when vicinallyattached to another ring forms a benzene-like ring—for exampletetrahydronapthalene, indole and the like.

The terms “oxo” and “thioxo” represent the groups ═O (as in carbonyl)and ═S (as in thiocarbonyl), respectively.

As used herein the term “alkyl” as a group or part of a group refers toa straight or branched chain saturated aliphatic hydrocarbon radicalcontaining 1 to 12 carbon atoms, suitably 1 to 6 carbon atoms. Suchalkyl groups in particular include methyl (“Me”), ethyl (“Et”), n-propyl(“Pr^(n)”), iso-propyl (“Pr^(i)”), n-butyl (“Bu^(n)”), sec-butyl(“Bu^(s)”), tert-butyl (“Bu^(t)”), pentyl and hexyl. Where appropriate,such alkyl groups may be substituted by one or more groups selected fromhalo (such as fluoro, chloro, bromo), —CN, —CF₃, —OH, —OCF₃,C₂₋₆alkenyl, C₃₋₆alkynyl, C₁₋₆alkoxy, aryl and di-C₁₋₆alkylamino.

As used herein, the term “alkoxy” as a group or part of a group refersto an alkyl ether radical, wherein the term “alkyl” is defined above.Such alkoxy groups in particular include methoxy, ethoxy, n-propoxy,iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy and tert-butoxy. Whereappropriate, such alkoxy groups may be substituted by one or more groupsselected from halo (such as fluoro, chloro, bromo), —CN, —CF₃, —OH,—OCF₃, C₁₋₆alkyl, C₂₋₆alkenyl, C₃₋₆alkynyl, aryl and di-C₁₋₆alkylamino.

As used herein, the term “aryl” as a group or part of a group refers toa carbocyclic aromatic radical (“Ar”). Suitably such aryl groups are 5-6membered monocyclic groups or 8-10 membered fused bicyclic groups,especially phenyl (“Ph”), biphenyl and naphthyl, particularly phenyl.

As used herein, the term “heteroaryl” as a group or part of a grouprefers to a stable 5-7-membered monocyclic or 7- to 10-membered bicyclicheterocyclic aromatic ring which consists of carbon atoms and from 1 to4 heteroatoms independently selected from the group consisting of N, Oand S. It is preferred that the total number of S and O atoms in thearomatic heterocycle is not more than 1. Examples of suitable heteroarylgroups include, but are not limited to, acridinyl, azocinyl,benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl,benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl,benzisoxazolyl, benzisothiazolyl, benzimidazolyl, carbazolyl,carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl,2H,6H-1,5,2-dithiazinyl, dihydrobenzofuranyl, furanyl, furazanyl,imidazolyl, 1H-indazolyl, indolinyl, indolyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolyl, isoquinolinyl, isothiazolyl,isoxazolyl, naphthyridinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolyl,pyrimidinyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyrazolyl,pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridyl, pyrrolyl,quinazolinyl, quinolinyl, quinoxalinyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thiazolyl,thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, triazinyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5 triazolyl, 1,3,4-triazolyl andxanthenyl.

As used herein, the terms “heterocyclyl” and “heterocyclic” as a groupor part of a group refer to stable heterocyclic non-aromatic single andfused rings containing one or more heteroatoms independently selectedfrom nitrogen, oxygen and sulfur. A fused heterocyclyl ring system mayinclude carbocyclic rings and need include only one heterocyclic ring.Examples of suitable heterocyclyl groups include, but are not limitedto, piperazinyl, homopiperazinyl, piperidinyl, pyrrolidinyl andmorpholinyl.

“Halo” or “halogen” means a halogen atoms selected from F, Cl, Br and I.

“C_(V-W)haloalkyl” means an alkyl group, as described above, wherein anynumber—at least one—of the hydrogen atoms attached to the alkyl chainare replaced by F, Cl, Br or I.

“Heterocycle” means a ring comprising at least one carbon atom and atleast one other atom selected from N, O and S. Examples of heterocyclesthat may be found in the claims include, but are not limited to, thefollowing:

“Available nitrogen atoms” are those nitrogen atoms that are part of aheterocycle and are joined by two single bonds (e.g. piperidine),leaving an external bond available for substitution by, for example, Hor CH₃.

“Pharmaceutically-acceptable salt” means a salt prepared by conventionalmeans, and are well known by those skilled in the art. The“pharmacologically acceptable salts” include basic salts of inorganicand organic acids, including but not limited to hydrochloric acid,hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid,ethanesulfonic acid, malic acid, acetic acid, oxalic acid, tartaricacid, citric acid, lactic acid, fumaric acid, succinic acid, maleicacid, salicylic acid, benzoic acid, phenylacetic acid, mandelic acid andthe like. When compounds of the invention include an acidic functionsuch as a carboxy group, then suitable pharmaceutically acceptablecation pairs for the carboxy group are well known to those skilled inthe art and include alkaline, alkaline earth, ammonium, quaternaryammonium cations and the like. For additional examples of“pharmacologically acceptable salts,” see infra and Berge et al., J.Pharm. Sci. 66: 1 (1977).

“Saturated or unsaturated” includes substituents saturated withhydrogens, substituents completely unsaturated with hydrogens andsubstituents partially saturated with hydrogens.

“Leaving group” generally refers to groups readily displaceable by anucleophile, such as an amine, a thiol or an alcohol nucleophile. Suchleaving groups are well known in the art. Examples of such leavinggroups include, but are not limited to, N-hydroxysuccinimide,N-hydroxybenzotriazole, halides, triflates, tosylates and the like.Preferred leaving groups are indicated herein where appropriate.

“Protecting group” generally refers to groups well known in the artwhich are used to prevent selected reactive groups, such as carboxy,amino, hydroxy, mercapto and the like, from undergoing undesiredreactions, such as nucleophilic, electrophilic, oxidation, reduction andthe like. Preferred protecting groups are indicated herein whereappropriate. Examples of amino protecting groups include, but are notlimited to, aralkyl, substituted aralkyl, cycloalkenylalkyl andsubstituted cycloalkenyl alkyl, allyl, substituted allyl, acyl,alkoxycarbonyl, aralkoxycarbonyl, silyl and the like. Examples ofaralkyl include, but are not limited to, benzyl, ortho-methylbenzyl,trityl and benzhydryl, which can be optionally substituted with halogen,alkyl, alkoxy, hydroxy, nitro, acylamino, acyl and the like, and salts,such as phosphonium and ammonium salts. Examples of aryl groups includephenyl, naphthyl, indanyl, anthracenyl, 9-(9-phenylfluorenyl),phenanthrenyl, durenyl and the like. Examples of cycloalkenylalkyl orsubstituted cycloalkylenylalkyl radicals, preferably have 6-10 carbonatoms, include, but are not limited to, cyclohexenyl methyl and thelike. Suitable acyl, alkoxycarbonyl and aralkoxycarbonyl groups includebenzyloxycarbonyl, t-butoxycarbonyl, iso-butoxycarbonyl, benzoyl,substituted benzoyl, butyryl, acetyl, trifluoroacetyl, trichloro acetyl,phthaloyl and the like. A mixture of protecting groups can be used toprotect the same amino group, such as a primary amino group can beprotected by both an aralkyl group and an aralkoxycarbonyl group. Aminoprotecting groups can also form a heterocyclic ring with the nitrogen towhich they are attached, for example, 1,2-bis(methylene)benzene,phthalimidyl, succinimidyl, maleimidyl and the like and where theseheterocyclic groups can further include adjoining aryl and cycloalkylrings. In addition, the heterocyclic groups can be mono-, di- ortrisubstituted, such as nitrophthalimidyl. Amino groups may also beprotected against undesired reactions, such as oxidation, through theformation of an addition salt, such as hydrochloride, toluenesulfonicacid, trifluoroacetic acid and the like. Many of the amino protectinggroups are also suitable for protecting carboxy, hydroxy and mercaptogroups. For example, aralkyl groups. Alkyl groups are also suitablegroups for protecting hydroxy and mercapto groups, such as tert-butyl.

Silyl protecting groups are silicon atoms optionally substituted by oneor more alkyl, aryl and aralkyl groups. Suitable silyl protecting groupsinclude, but are not limited to, trimethylsilyl, triethylsilyl,triisopropylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl,1,2-bis(dimethylsilyl)benzene, 1,2-bis(dimethylsilyl)ethane anddiphenylmethylsilyl. Silylation of an amino groups provide mono- ordi-silylamino groups. Silylation of aminoalcohol compounds can lead to aN,N,O-trisilyl derivative. Removal of the silyl function from a silylether function is readily accomplished by treatment with, for example, ametal hydroxide or ammonium fluoride reagent, either as a discretereaction step or in situ during a reaction with the alcohol group.Suitable silylating agents are, for example, trimethylsilyl chloride,tert-butyl-dimethylsilyl chloride, phenyldimethylsilyl chloride,diphenylmethyl silyl chloride or their combination products withimidazole or DMF. Methods for silylation of amines and removal of silylprotecting groups are well known to those skilled in the art. Methods ofpreparation of these amine derivatives from corresponding amino acids,amino acid amides or amino acid esters are also well known to thoseskilled in the art of organic chemistry including amino acid/amino acidester or aminoalcohol chemistry.

Protecting groups are removed under conditions which will not affect theremaining portion of the molecule. These methods are well known in theart and include acid hydrolysis, hydrogenolysis and the like. Apreferred method involves removal of a protecting group, such as removalof a benzyloxycarbonyl group by hydrogenolysis utilizing palladium oncarbon in a suitable solvent system such as an alcohol, acetic acid, andthe like or mixtures thereof. A t-butoxycarbonyl protecting group can beremoved utilizing an inorganic or organic acid, such as HCl ortrifluoroacetic acid, in a suitable solvent system, such as dioxane ormethylene chloride. The resulting amino salt can readily be neutralizedto yield the free amine. Carboxy protecting group, such as methyl,ethyl, benzyl, tert-butyl, 4-methoxyphenylmethyl and the like, can beremoved under hydrolysis and hydrogenolysis conditions well known tothose skilled in the art.

It should be noted that compounds of the invention may contain groupsthat may exist in tautomeric forms, such as cyclic and acyclic amidineand guanidine groups, heteroatom substituted heteroaryl groups (Y′=O, S,NR), and the like, which are illustrated in the following examples:

and though one form is named, described, displayed and/or claimedherein, all the tautomeric forms are intended to be inherently includedin such name, description, display and/or claim.

Prodrugs of the compounds of this invention are also contemplated bythis invention. A prodrug is an active or inactive compound that ismodified chemically through in vivo physiological action, such ashydrolysis, metabolism and the like, into a compound of this inventionfollowing administration of the prodrug to a patient. The suitabilityand techniques involved in making and using prodrugs are well known bythose skilled in the art. For a general discussion of prodrugs involvingesters see Svensson and Tunek Drug Metabolism Reviews 165 (1988) andBundgaard Design of Prodrugs, Elsevier (1985). Examples of a maskedcarboxylate anion include a variety of esters, such as alkyl (forexample, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl(for example, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (forexample, pivaloyloxymethyl). Amines have been masked asarylcarbonyloxymethyl substituted derivatives which are cleaved byesterases in vivo releasing the free drug and formaldehyde (Bungaard J.Med. Chem. 2503 (1989)). Also, drugs containing an acidic NH group, suchas imidazole, imide, indole and the like, have been masked withN-acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)).Hydroxy groups have been masked as esters and ethers. EP 039,051 (Sloanand Little, Apr. 11, 1981) discloses Mannich-base hydroxamic acidprodrugs, their preparation and use.

The specification and claims contain listing of species using thelanguage “selected from . . . and . . . ” and “is . . . or . . . ”(sometimes referred to as Markush groups). When this language is used inthis application, unless otherwise stated it is meant to include thegroup as a whole, or any single members thereof, or any subgroupsthereof. The use of this language is merely for shorthand purposes andis not meant in any way to limit the removal of individual elements orsubgroups as needed.

EXPERIMENTAL

Unless otherwise noted, all materials were obtained from commercialsuppliers and used without further purification. All parts are by weightand temperatures are in degrees centigrade unless otherwise indicated.All microwave assisted reactions were conducted with a Smith Synthesizerfrom Personal Chemistry, Uppsala, Sweden. All compounds showed NMRspectra consistent with their assigned structures. Melting points weredetermined on a Buchi apparatus and are uncorrected. Mass spectral datawas determined by electrospray ionization technique. All examples werepurified to >90% purity as determined by high-performance liquidchromatography. Unless otherwise stated, reactions were run at roomtemperature.

The following abbreviations are used:

-   DMSO—dimethyl sulfoxide-   DMF—N,N-dimethylformamide-   THF—tetrahydrofuran-   Et₂O—diethyl ether-   EtOAc—ethyl acetate-   MeOH—methyl alcohol-   EtOH—ethyl alcohol-   MeCN—acetonitrile-   MeI—iodomethane-   NMP—1-methyl-2-pyrrolidinone-   DCM—dichloromethane-   TFA—trifuoroacetic acid-   Sat.—saturated-   h—hour-   min—minutes

Example 1

(a) 4-(3-Trifluoromethyl-pyridin-2-yl)-benzoic acid. A mixture of2-chloro-3-trifluoromethyl-pyridine (362 mg, 2 mmol, TCI America),4-carboxyphenyl boronic acid (365 mg, 2.2 mmol, Aldrich), Pd(PPh₃)₄ (162mg, 0.14 mmol, Aldrich) and 2 N Na₂CO₃ (4 mL) in dioxane (3 mL) washeated in a microwave synthesizer at 140° C. for 15 min. The reactionmixture was diluted with water (2 mL) and 1 N NaOH (2 mL), and extractedwith diethyl ether (20 mL). The aqueous layer was separated, acidifiedwith 2 N HCl and extracted with EtOAc (2×20 mL). The combined organicextracts were washed with brine, dried over MgSO₄, and filtered. Thefiltrate was evaporated in vacuo and the residue was purified by silicagel column chromatography (gradient, 5 to 10% MeOH/EtOAc) to provide thetitle compound as an off-white solid. MS (ESI, pos. ion) m/z: 268 (M+1).

(b) 4-(3-Trifluoromethyl-pyridin-2-yl)-benzoyl chloride hydrochloride.To a mixture of 4-(3-trifluoromethyl-pyridin-2-yl)-benzoic acid, Example1(a), (367 mg, 1.37 mmol) and CH₂Cl₂ (3 mL) was added oxalyl chloride(1.37 mL, 2 M solution in CH₂Cl₂, 2.74 mmol, Aldrich) and DMF (2 drops)with stirring at 0° C. The reaction mixture was stirred at roomtemperature for 3 h and the solvents were removed in vacuo to give thetitle compound as a solid, which was used in the next step withoutpurification.

(c) N-Quinolin-7-yl-4-(3-trifluoromethyl-pyridin-2-yl)-benzamide. Amixture of 4-(3-trifluoromethyl-pyridin-2-yl)-benzoyl chloridehydrochloride, Example 1(b), (258 mg, 0.9 mmol), 7-aminoquinoline,prepared according to the procedure described in WO03099284, (116 mg,0.8 mmol) and pyridine (3 mL) was stirred at room temperature for 6 h.The reaction mixture was evaporated in vacuo and the residue waspartitioned between EtOAc (30 mL) and saturated NaHCO₃ (5 mL). Theorganic phase was separated, dried over MgSO₄, and filtered. Thefiltrate was evaporated in vacuo and the residue was purified by silicagel column chromatography (gradient, 30 to 70% EtOAc/hexane) to providethe title compound as an off-white amorphous solid. MS (ESI, pos. ion)m/z: 394 (M+1).

Example 2

(a) 6-Bromo-naphthalene-2-carbonyl chloride. To a mixture of6-bromo-naphthalene-2-carboxylic acid (1 g, 3.9 mmol, Lancaster) andCH₂Cl₂ (25 mL) was added oxalyl chloride (2.98 mL, 2 M solution inCH₂Cl₂, 5.8 mmol, Aldrich) and DMF (2 drops) with stirring at 0° C. Thereaction mixture was stirred at room temperature for 18 h and thesolvents were removed in vacuo to afford the title compound as alight-brown amorphous solid, which was used in the next step withouthpurification. MS (ESI, pos. ion) m/z: 266 (M+1).

(b) 6-Bromo-naphthalene-2-carboxylic acid(3-hydroxymethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-amide. Thismaterial was prepared analogous to the procedure described for Example1(c). 6-Bromo-naphthalene-2-carbonyl chloride, Example 2(a), (147 mg,0.54 mmol) reacted with7-amino-3-hydroxymethyl-3,4-dihydro-1H-quinolin-2-one (104 mg, 0.54mmol, prepared according to the procedure described in WO03049702) togive the title compound as an off-white amorphous solid. MS (ESI, pos.ion) m/z: 427 (M+1).

Example 3

6-Bromo-naphthalene-2-carboxylic acid(3-hydroxymethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-amide. This materialwas prepared analogous to the procedure described for Example 1(c).6-Bromo-naphthalene-2-carbonyl chloride, Example 2(a), (258 mg, 0.96mmol) reacted with (7-amino-1,2,3,4-tetrahydro-quinolin-3-yl)-methanol(171 mg, 0.96 mmol, prepared according to the procedure described inWO03049702) to give the title compound as an light-brown amorphoussolid. MS (ESI, pos. ion) m/z: 413 (M+1).

Example 4

2,2-Dimethyl-chroman-6-carboxylic acid(3-hydroxymethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-amide. Thismaterial was prepared analogous to the procedures described for Example2, steps (a-b). 2,2-Dimethyl-chroman-6-carboxylic acid (90 mg, 0.4 mmol,Maybridge) and 7-amino-3-hydroxymethyl-3,4-dihydro-1H-quinolin-2-one (85mg, 0.44 mmol, prepared according to the procedure described inWO03049702) provided the title compound as an off-white amorphous solid.MS (ESI, pos. ion) m/z: 381 (M+1).

Example 5

Naphthalene-2-carboxylic acid quinolin-7-ylamide. This material wasprepared analogous to the procedure described for Example 1(c).2-Naphthoyl chloride (200 mg, 1 mmol, Aldrich) reacted with7-amino-quinoline (102 mg, 0.95 mmol, prepared according to theprocedure described in WO03099284) to give the title compound as anoff-white amorphous solid. MS (ESI, pos. ion) m/z: 299 (M+1).

Example 6

(a) 6-Trifluoromethyl-thieno[3,2-b]pyridine-2-carboxylic acid. To a250-mL, round-bottomed flask, equipped with magnetic stirring, was addedethyl 6-(trifluoromethyl)-thieno-[3,2-b]-pyrimidine-2-carboxylate (1.0g, 3.6 mmol, Maybridge), 5 N NaOH (8 mL) and THF (8 mL). The reactionmixture was stirred at room temperature for 7 h. The mixture wasacidified to pH 5 by adding 10% HCl and the product was extracted withEtOAc (25 mL). The organic phase was washed with H₂O (2×15 mL), driedover Na₂SO₄, filtered, and concentrated in vacuo to yield the titlecompound as a white solid. MS (ESI, pos. ion) m/z: 248 (M+1).

(b) 6-Trifluoromethyl-thieno[3,2-b]pyridine-2-carboxylic acidquinolin-7-ylamide. To a 50-mL, round-bottomed flask equipped with amagnetic stirring bar was added6-trifluoromethyl-thieno[3,2-b]pyridine-2-carboxylic acid, Example 6(a),(0.20 g, 0.81 mmol), DMF (8 mL), 7-aminoquinoline (0.12 g, 0.85 mmol,prepared according to the procedure described in WO03099284),dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (0.23 g, 1.2 mmol,Aldrich) and N,N-diisopropylethylamine (0.44 mL, 2.6 mmol, Aldrich). Thereaction mixture was stirred at 25° C. for 18 h and concentrated invacuo. The residue was dissolved in EtOAc (20 mL), washed with H₂O (2×15mL), dried over Na₂SO₄, and filtered. The filtrate was concentrated invacuo and the residue was purified by silica gel column chromatography(EtOAc) to give the title compound as a white solid. MP 296° C. MS (ESI,pos. ion) m/z: 374 (M+1).

Example 7

(a) 6-Trifluoromethyl-benzo[b]thiophene-2-carbonyl chloride. Thismaterial was prepared analogous to the procedure described for Example1(a). 6-Trifluoromethyl-benzo[b]thiophene-2-carboxylic acid (220 mg,0.89 mmol, prepared according to the procedure described in EP483647)reacted with oxalyl chloride (0.89 mL, 2 M solution in CH₂Cl₂, 1.78mmol, Aldrich) to give the title compound, which was used in the nextstep without purification.

(b) 6-Trifluoromethyl-benzo[b]thiophene-2-carboxylic acidquinolin-7-ylamide. This material was prepared analogous to theprocedure described for Example 1(c).6-Trifluoromethyl-benzo[b]thiophene-2-carbonyl chloride, Example 7(a),(146 mg, 0.55 mmol) reacted with 7-amino-quinoline (1.22 g, 8.5 mmol,prepared according to the procedure described in WO03099284) to give thetitle compound as an off-white solid. Mp 229.7° C. MS (ESI, pos. ion)m/z: 373 (M+1).

Example 8

(a) 5-Trifluoromethyl-benzo[b]thiophene-2-carbonyl chloride. Thismaterial was prepared analogous to the procedure described for Example 1(a). 5-Trifluoromethyl-benzo[b]thiophene-2-carboxylic acid (244 mg, 1mmol, Bionet) reacted with oxalyl chloride (1 mL, 2 M solution inCH₂Cl₂, 2 mmol, Aldrich) to give the title compound, which was used inthe next step without purification.

(b) 5-Trifluoromethyl-benzo[b]thiophene-2-carboxylic acidquinolin-7-ylamide. This material was prepared analogous to theprocedure described for Example 1(c).5-Trifluoromethyl-benzo[b]thiophene-2-carbonyl chloride, Example 8(a),(146 mg, 1 mmol) reacted with 7-amino-quinoline (130 mg, 0.9 mmol,prepared according to the procedure described in WO03099284) to give thetitle compound as an off-white amorphous solid. MS (ESI, pos. ion) m/z:373 (M+1).

Example 9

(a) 3-Pyridin-4-yl-6-trifluoromethyl-thieno[3,2-b]pyridine-2-carbonylchloride hydrochloride. This material was prepared analogous to theprocedure described for Example 1(a).3-Pyridin-4-yl-6-trifluoromethyl-thieno[3,2-b]pyridine-2-carboxylic acid(91 mg, 0.28 mmol, Bionet) reacted with oxalyl chloride (0.28 mL, 2 Msolution in CH₂Cl₂, 0.56 mmol, Aldrich) to give the title compound,which was used in the next step without purification.

(b) 3-Pyridin-4-yl-6-trifluoromethyl-thieno[3,2-b]pyridine-2-carboxylicacid quinolin-7-ylamide. This material was prepared analogous to theprocedure described for Example 1(c).3-Pyridin-4-yl-6-trifluoromethyl-thieno[3,2-b]pyridine-2-carbonylchloride hydrochloride, Example 9(a), (0.28 mmol) reacted with7-amino-quinoline (36 mg, 0.25 mmol, prepared according to the proceduredescribed in WO03099284) to give the title compound as a brown film. MS(ESI, pos. ion) m/z: 451 (M+1).

Example 10

(a) 3-Furan-2-yl-6-trifluoromethyl-thieno[3,2-b]pyridine-2-carbonylchloride hydrochloride. This material was prepared analogous to theprocedure described for Example 1(a).3-Furan-2-yl-6-trifluoromethyl-thieno[3,2-b]pyridine-2-carboxylic acid(88 mg, 0.28 mmol, Bionet) reacted with oxalyl chloride (0.28 mL, 2 Msolution in CH₂Cl₂, 0.56 mmol, Aldrich) to give the crude titlecompound, which was used in the next step without purification.

(b) 3-Furan-2-yl-6-trifluoromethyl-thieno[3,2-b]pyridine-2-carboxylicacid quinolin-7-ylamide. This material was prepared analogous to theprocedure described for Example 1 (c).3-Furan-2-yl-6-trifluoromethyl-thieno[3,2-b]pyridine-2-carbonyl chloridehydrochloride (the crude product of Example 10(a), ˜0.28 mmol) reactedwith 7-amino-quinoline (36 mg, 0.25 mmol, prepared according to theprocedure described in WO03099284) to give the title compound as alight-yellow amorphous solid. MS (ESI, pos. ion) m/z: 440 (M+1).

Example 11

(a) 5-Bromo-1-methyl-1H-indole-2-carboxylic acid methyl ester. A mixtureof 5-bromo-1H-indole-2-carboxylic acid (179 mg, 0.74 mmol, Sigma),1,4-diazabicyclo[2.2.2]octane (92 mg, 0.81 mmol, Aldrich) and dimethylcarbonate (2 mL, Aldrich) was heated at 90° C. for 18 h. The reactionmixture was partitioned between 1 N HCl (5 mL) and EtOAc (50 mL). Theorganic phase was separated, dried over MgSO₄, and filtered. Thefiltrate was evaporated in vacuo to give the crude title compound as athick brown oil, which was used in the next step without purification.MS (ESI, pos. ion) m/z: 269 (M+1).

(b) 5-Bromo-1-methyl-1H-indole-2-carboxylic acid. A mixture of5-bromo-1-methyl-1H-indole-2-carboxylic acid methyl ester (the crudeproduct of Example 11(a), ˜0.74 mmol), LiOH (36 mg, 1.49 mmol), MeOH (2mL) and water (1 mL) was heated at 85° C. for 35 min. The reactionmixture was cooled to room temperature, acidified with 1 N HCl andextracted with EtOAc (2×15 mL). The EtOAc extracts were combined, driedover MgSO₄, and filtered. The filtrate was evaporated in vacuo to givethe title compound as an off-white solid. MS (ESI, pos. ion) m/z: 255(M+1).

(c) 5-Bromo-1-methyl-1H-indole-2-carbonyl chloride. This material wasprepared analogous to the procedure described for Example 1(a).5-Bromo-1-methyl-1H-indole-2-carboxylic acid, Example 11(b), (128 mg,0.5 mmol) reacted with oxalyl chloride (0.5 mL, 2 M solution in CH₂Cl₂,1 mmol, Aldrich) to give the crude title compound, which was used in thenext step without purification.

(d) 1-Methyl-1H-indole-2-carboxylic acid quinolin-7-ylamide. Thismaterial was prepared analogous to the procedure described for Example1(c). 5-Bromo-1-methyl-1H-indole-2-carbonyl chloride (the crude productof Example 11(c), ˜0.5 mmol) reacted with 7-amino-quinoline (66 mg, 0.45mmol, prepared according to the procedure described in WO03099284) togive the title compound as an off-white solid. Mp 253.0-253.9° C. MS(ESI, pos. ion) m/z: 381 (M+1).

Example 12

6-Bromo-1H-indole-2-carboxylic acid quinolin-7-ylamide. This materialwas prepared analogous to the procedure described for Example 6(b).6-Bromo-1H-indole-2-carboxylic acid (208 mg, 0.87 mmol, Asymchem)reacted with 7-amino-quinoline (125 mg, 0.87 mmol, prepared according tothe procedure described in WO03099284) to give the title compound as alight-brown amorphous solid. MS (ESI, pos. ion) m/z: 366 (M+1).

Additional Examples

Table 1. The following examples were prepared from 7-amino-quinoline(prepared according to the procedure described in WO030992841) andcommercially available carboxylic acids according to the proceduresdescribed for the preparation of Example 11, steps (c-d). TABLE 1 Thefollowing examples were prepared from 7-amino-quinoline (preparedaccording to the procedure described in WO030992841) and commerciallyavailable carboxylic acids according to the procedures described for thepreparation of Example 11, steps (c-d). Ex. Structure Melt Point (° C.)M.S. (ESI) m/z 13

amorphous solid 380 (M + 1) 14

amorphous solid 302 (M + 1) 15

amorphous solid 378 (M + 1)

Example 16

(a) 3-Bromo-1H-indole-6-carboxylic acid methyl ester. To a solution ofindole-6-carboxylic acid methyl ester (2 g, 11.4 mmol, Acros) in DMF (40mL) was added dropwise bromine (2 g, 12.5 mmol, Aldrich) with stiiringat room temperature. The reaction mixture was stirred at roomtemperature for 10 min and quenched with ice-water (200 mL), 0.5% aq.solution of ammonium hydroxide, and 0.1% aq. solution of sodiumthiosulphate. The solid precipitate was filtered, washed with water(2×40 mL) and air dried to afford the title compound as a whiteamorphous solid. MS (ESI, pos. ion) m/z: 255 (M+1).

(b) 3-Bromo-1H-indole-6-carboxylic acid. This material was preparedanalogous to the procedure described for Example 11(b).3-Bromo-1H-indole-6-carboxylic acid methyl ester, Example 16(a), (400mg, 1.6 mmol) reacted with LiOH (75 mg, 3.2 mmol) to give the titlecompound as a brown amorphous solid. MS (ESI, pos. ion) m/z: 242 (M+1).

(c) 3-Bromo-1H-indole-6-carboxylic acid quinolin-7-ylamide. Thismaterial was prepared analogous to the procedure described for Example6(b). 3-Bromo-1H-indole-6-carboxylic acid, Example 16(b), (201 mg, 0.83mmol) reacted with 7-amino-quinoline (120 mg, 0.83 mmol, preparedaccording to the procedure described in WO03099284) to give the titlecompound as an off-white amorphous solid. MS (ESI, pos. ion) m/z: 368(M+1).

Example 17

3-Bromo-1-methyl-1H-indole-6-carboxylic acid quinolin-7-ylamide. Thismaterial was prepared analogous to the procedures described for Example11, steps (a-d), starting from 3-bromo-1H-indole-6-carboxylic acid(Example 16(b)). The title compound was isolated as a brown amorphoussolid. MS (ESI, pos. ion) m/z: 382 (M+1).

Example 18

3-Bromo-1-(2-dimethylamino-ethyl)-1H-indole-6-carboxylic acidquinolin-7-ylamide, trifluoroacetic acid salt. To a solution of3-bromo-1H-indole-6-carboxylic acid quinolin-7-ylamide, Example 16(c),(100 mg, 0.27 mmol) in DMF (5 mL) was added sodium hydride (13 mg, 0.547mmol, Aldrich), and the reaction mixture was stirred at room temperaturefor 1 h. 2-(Dimethylamino)ethyl chloride hydrochloride (33 mg, 0.3 mmol,Aldrich) was added, and the mixture was stirred at room temperature for18 h. The reaction mixture was diluted with EtOAc and washed withsaturated NH₄Cl. The EtOAc layer was separated, washed with brine, driedover MgSO₄, and filtered. The filtrate was evaporated in vacuo and theresidue was purified by preparative HPLC (gradient 0.1% TFA in CH₃CN) toprovide the title compound as brown film. MS (ESI, pos. ion) m/z: 438(M+1).

Example 19

(a) 1-Benzyl-3-bromo-1H-indole-6-carboxylic acid methyl ester. To asolution of 3-bromo-1H-indole-6-carboxylic acid methyl ester Example16(a), (250 mg, 0.98 mmol) in DMF (2.5 mL) was added dropwise asuspension of sodium hydride (29 mg, 1.2 mmol, Aldrich) in DMF (2.5 mL),and the reaction mixture was stirred at 0° C. for 1 h. Benzyl chloride(131 mg, 1.04 mmol, Aldrich) was added, and the mixture was stirred atroom temperature for 18 h. The reaction mixture was evaporated in vacuoand the residue was diluted with EtOAc (50 mL), washed with brine, driedover MgSO₄, and filtered. The filtrate was evaporated in vacuo toprovide the title compound as an off-white amorphous solid. MS (ESI,pos. ion.) m/z: 346 (M+1).

(b) 1-Benzyl-3-bromo-1H-indole-6-carboxylic acid. This material wasprepared analogous to the procedure described for Example 11(b).1-Benzyl-3-bromo-1H-indole-6-carboxylic acid methyl ester, Example 19(a)reacted with LiOH to give the title compound as an amorphous solid.

(c) 1-Benzyl-3-bromo-1H-indole-6-carboxylic acid quinolin-7-ylamide.This material was prepared analogous to the procedure described forExample 6(b). 1-Benzyl-3-bromo-1H-indole-6-carboxylic acid, Example19(b), (60 mg, 0.18 mmol) reacted with 7-amino-quinoline (26 mg, 0.18mmol, prepared according to the procedure described in WO03099284) togive the title compound as a brown amorphous solid. MS (ESI, pos. ion)m/z: 458 (M+1).

Example 20

1-Benzyl-6-bromo-1H-indole-2-carboxylic acid quinolin-7-ylamide. Thismaterial was prepared analogous to the procedures described for Example19, steps (b-c) starting from 6-bromo-1H-indole-2-carboxylic acid ethylester (Asymchem). The title compound was isolated as a light-yellowamorphous solid. MS (ESI, pos. ion) m/z: 458 (M+1).

Example 21

1-Benzyl-5-bromo-1H-indole-2-carboxylic acid quinolin-7-ylamide. Thismaterial was prepared analogous to the procedures described for Example19, steps (a-c) starting from 5-bromo-1H-indole-2-carboxylic acid ethylester (Asymchem). The title compound was isolated as an off-whiteamorphous solid. MS (ESI, pos. ion) m/z: 458 (M+1).

Example 22

(a)2-(3-Trifluoromethyl-pyridin-2-yl)-1,2,3,4-tetrahydro-isoquinoline-6-carboxylicacid methyl ester. To a solution of1,2,3,4-tetrahydro-isoquinoline-6-carboxylic acid methyl ester (287 mg,1.5 mmol, Arch) and 2-chloro-3-trifluoromethyl-pyridine (298 mg, 1.65mmol, TCI America) in DMF (5 mL) was added K₂CO₃ (310 mg, 2.25 mmol),and the resulting mixture was heated at 80° C. for 10 h. The reactionmixture was cooled to room temperature and concentrated in vacuo. Theresidue was partitioned between 2 N HCl (5 mL) and EtOAc (40 mL). TheEtOAc layer was separated, washed with brine, dried over MgSO₄, andfiltered. The filtrate was evaporated in vacuo and the residue waspurified by silica gel column chromatography (gradient, 15 to 60%EtOAc/hexane) to provide the title compound as a colorless oil. MS (ESI,pos. ion) m/z: 337 (M+1).

(b)2-(3-Trifluoromethyl-pyridin-2-yl)-1,2,3,4-tetrahydro-isoquinoline-6-carboxylicacid. This material was prepared analogous to the procedure describedfor Example 11(b).2-(3-Trifluoromethyl-pyridin-2-yl)-1,2,3,4-tetrahydro-isoquinoline-6-carboxylicacid methyl ester, Example 22(a), (128 mg, 0.5 mmol) reacted with LiOH(50 mg, 2.08 mmol) to give the title compound as a white solid. MS (ESI,pos. ion) m/z: 323 (M+1).

(c)2-(3-Trifluoromethyl-pyridin-2-yl)-1,2,3,4-tetrahydro-isoquinoline-6-carbonylchloride hydrochloride. This material was prepared analogous to theprocedure described for Example 1(a).2-(3-Trifluoromethyl-pyridin-2-yl)-1,2,3,4tetrahydro-isoquinoline-6-carboxylicacid, Example 22(b), (250 mg, 0.77 mmol) reacted with oxalyl chloride(0.77 mL, 2 M solution in CH₂Cl₂, 1.54 mmol, Aldrich) to give the titlecompound, which was used in the next step without purification.

(d)2-(3-Trifluoromethyl-pyridin-2-yl)-1,2,3,4-tetrahydro-isoquinoline-6-carboxylicacid quinolin-7-ylamide. This material was prepared analogous to theprocedure described for Example 1(c).2-(3-Trifluoromethyl-pyridin-2-yl)-1,2,3,4-tetrahydro-isoquinoline-6-carbonylchloride hydrochloride, Example 22(c), (0.77 mmol) reacted with7-amino-quinoline (112 mg, 0.77 mmol, prepared according to theprocedure described in WO03099284) to give the title compound as anoff-white film. MS (ESI, pos. ion) m/z: 449 (M+1).

Example 23

(a) 2-(1-Phenyl-ethyl)-1,2,3,4-tetrahydro-isoquinoline-6-carboxylicacid. To a solution of 1,2,3,4-tetrahydro-isoquinoline-6-carboxylic acidmethyl ester (191 mg, 1.0 mmol, Arch) in DMF (1 mL) and THF (2 mL) at 0°C. was added NaH (51 mg, 95%, 2.0 mmol, Aldrich) and(1-bromoethyl)benzene (195 mg, 1.05 mmol, Aldrich), and the resultingmixture was stirred at room temperature for 3 h. The reaction mixturewas diluted with satd NH₄Cl (5 mL) and EtOAc (5 mL), which led to theprecipitation of an off-white solid. The solid was filtered, washed withwater (2 mL) and EtOAc (2 mL), and dried in vacuo to provide the titlecompound. MS (ESI, pos. ion.) m/z: 282 (M+1).

(b) 2-(1-Phenyl-ethyl)-1,2,3,4-tetrahydro-isoquinoline-6-carbonylchloride hydrochloride. This material was prepared analogous to theprocedure described for Example 1(a).2-(1-Phenyl-ethyl)-1,2,3,4-tetrahydro-isoquinoline-6-carboxylic acid,Example 23(a), (126 mg, 0.45 mmol) reacted with oxalyl chloride (0.45mL, 2 M solution in CH₂Cl₂, 1.54 mmol, Aldrich) to give the crude titlecompound, which was used in the next step without purification.

(c) 2-(1-Phenyl-ethyl)-1,2,3,4-tetrahydro-isoquinoline-6-carboxylic acidquinolin-7-ylamide. This material was prepared analogous to theprocedure described for Example 1(c).2-(1-Phenyl-ethyl)-1,2,3,4-tetrahydro-isoquinoline-6-carbonyl chloridehydrochloride (the crude product of Example 23(b), ˜0.45 mmol) reactedwith 7-amino-quinoline (65 mg, 0.45 mmol, prepared according to theprocedure described in WO03099284) to give the title compound as a brownfilm. MS (ESI, pos. ion) m/z: 408 (M+1).

Example 24

2-Benzyl-1,2,3,4-tetrahydro-isoquinoline-6-carboxylic acidquinolin-7-ylamide. This material was prepared analogous to theprocedures described for Example 23, steps (a-c) starting from1,2,3,4-tetrahydro-isoquinoline-6-carboxylic acid methyl ester (Arch).The title compound was isolated as a brown amorphous solid. MS (ESI,pos. ion) m/z: 394 (M+1).

Example 25

(a)2-(2,2,2-Trifluoro-ethyl)-1,2,3,4-tetrahydro-isoquinoline-6-carboxylicacid methyl ester. A mixture of1,2,3,4-tetrahydro-isoquinoline-6-carboxylic acid methyl ester (187 mg,0.98 mmol, Arch), 2,2,2-trifluoro-ethanesulfonic acid trichloromethylester (357 mg, 1.27 mmol, Oakwood) and K₂CO₃ (405 mg, 2.94 mmol) inacetone (3 mL) was heated at 65° C. for 18 h. The reaction mixture wascooled to room temperature and concentrated in vacuo. The residue waspartitioned between water (10 mL) and EtOAc (50 mL). The EtOAc layer wasseparated, washed with brine, dried over MgSO₄, and filtered. Thefiltrate was evaporated in vacuo to give the title compound as a brownsolid. MS (ESI, pos. ion.) m/z: 274 (M+1).

(b) 2-(2,2,2-Trifluoro-ethyl)-1,2,3,4-tetrahydro-isoquinoline-6-carbonylchloride hydrochloride. A mixture of2-(2,2,2-trifluoro-ethyl)-1,2,3,4-tetrahydro-isoquinoline-6-carboxylicacid methyl ester, Example 25(a), (100 mg, 0.36 mmol), LiOH (18 mg, 0.75mmol), MeOH (2 mL) and water (2 mL) was heated in a microwavesynthesizer at 150° C. for 10 min. The reaction mixture was evaporatedin vacuo, the residue was suspended in toluene (20 mL), and the solventwas evaporated. The residue was suspended in toluene (20 mL) and thesolvent was evaporated to give a pale-yellow residue. To the residue wasadded CH₂Cl₂ (3 mL), oxalyl chloride (0.36 mL, 2 M solution in CH₂Cl₂,0.72 mmol, Aldrich) and DMF (1 drop), and the mixture was stirred atroom temperature for 3 h. The solvents were removed in vacuo to give thecrude title compound as a yellow solid, which was used in the next stepwithout purification.

(c)2-(2,2,2-Trifluoro-ethyl)-1,2,3,4-tetrahydro-isoquinoline-6-carboxylicacid quinolin-7-ylamide. This material was prepared analogous to theprocedure described for Example 1(c).2-(2,2,2-Trifluoro-ethyl)-1,2,3,4-tetrahydro-isoquinoline-6-carbonylchloride (the crude product of Example 25(b), ˜0.36 mmol) reacted with7-amino-quinoline (158 mg, 1.1 mmol, prepared according to the proceduredescribed in WO03099284) to give the title compound as a brown amorphoussolid. MS (ESI, pos. ion) m/z: 386 (M+1).

Example 26

(a) 2-Isopropyl-1,2,3,4-tetrahydro-isoquinoline-6-carboxylic acid methylester. A mixture of 1,2,3,4-tetrahydro-isoquinoline-6-carboxylic acidmethyl ester (166 mg, 0.87 mmol, Arch), acetone (0.5 mL), CH₃CN (0.5mL), MeOH (0.5 mL) and glacial acetic acid (1 drop) was heated at 80° C.for 30 min. The temperature of the reaction mixture was adjusted to 50°C., and sodium triacetoxyborohydride (1.11 g, 5.26 mmol, Aldrich) wasadded in small portions with stirring for 6 h. The mixture was cooled toroom temperature and partitioned between water (15 mL) and EtOAc (100mL). The EtOAc layer was separated, washed with brine, dried over MgSO₄,and filtered. The filtrate was evaporated in vacuo to give the titlecompound as a brown oil. MS (ESI, pos. ion.) m/z: 234 (M+1).

(b) 2-Isopropyl-1,2,3,4-tetrahydro-isoquinoline-6-carbonyl chloridehydrochloride. This material was prepared analogous to the proceduresdescribed for Example 25(b) starting from2-isopropyl-1,2,3,4-tetrahydro-isoquinoline-6-carboxylic acid methylester, Example 26(a), (100 mg, 0.43 mmol). The title compound wasisolated as a yellow solid and used in the next step withoutpurification.

(c) 2-Isopropyl-1,2,3,4-tetrahydro-isoquinoline-6-carboxylic acidquinolin-7-ylamide. This material was prepared analogous to theprocedure described for Example 1(c).2-Isopropyl-1,2,3,4-tetrahydro-isoquinoline-6-carbonyl chloridehydrochloride (the crude product of Example 26(b), ˜0.43 mmol) reactedwith 7-amino-quinoline (68 mg, 0.47 mmol, prepared according to theprocedure described in WO03099284) to give the title compound as a brownamorphous solid. MS (ESI, pos. ion) m/z: 346 (M+1).

Example 27

4-Bromo-N-quinolin-7-yl-benzamide. This material was prepared analogousto the procedure described for Example 1(c). 4-Bromo-benzoyl chloride(2.19 g, 10 mmol, Aldrich) reacted with 7-amino-quinoline (1.22 g, 8.5mmol, prepared according to the procedure described in WO03099284) togive the title compound. MS (ESI, pos. ion) m/z: 328 (M+1).

Example 28

2′-Formyl-biphenyl-4-carboxylic acid quinolin-7-ylamide. This materialwas prepared analogous to the procedure described for Example 1(a).4-Bromo-N-quinolin-7-yl-benzamide, Example 27, (327 mg, 1 mmol) reactedwith 2-formylphenyl boronic acid (183 mg, 1.1 mmol, Aldrich) to give thetitle compound as a yellow solid. Mp 258-260° C. MS (ESI, pos. ion)nz/z: 353 (M+1).

Example 29

2′-Hydroxymethyl-biphenyl-4-carboxylic acid quinolin-7-ylamide. To asolution of 2′-formyl-biphenyl-4-carboxylic acid quinolin-7-ylamide,Example 28, (90 mg, 0.25 mmol) in MeOH (2 mL) was added sodiumborohydride (20 mg, 0.51 mmol) and the mixture was stirred for 10 min at0° C. The reaction mixture was diluted with EtOAc (50 mL) and washedwith satd NH₄Cl (5 mL). The EtOAc layer was separated, washed withbrine, dried over MgSO₄, and filtered. The filtrate was evaporated invacuo and the residue was purified by silica gel column chromatography(gradient, 40 to 90% EtOAc/hexane) to provide the title compound as ayellow amorphous solid. MS (ESI, pos. ion.) m/z: 355 (M+1).

Example 30

2′-(2-Dimethylamino-ethoxymethyl)-biphenyl-4-carboxylic acidquinolin-7-ylamide, trifluoroacetic acid salt To a solution of2′-hydroxymethyl-biphenyl-4-carboxylic acid quinolin-7-ylamide, Example29, (60 mg, 0.17 mmol) in DMF (2 mL) was added sodium hydride (34 mg of95%, 1.34 mmol, Aldrich) and the mixture was stirred at 0° C. for 5 min.2-(Dimethylamino)ethyl chloride hydrochloride (49 mg, 0.34 mmol,Aldrich) was added, and the mixture was stirred at 80° C. for 2 h. Thereaction mixture was cooled to room temperature, diluted with EtOAc (50mL) and washed with saturated NH₄Cl (5 mL). The EtOAc layer wasseparated, washed with brine, dried over MgSO₄, and filtered. Thefiltrate was evaporated in vacuo and the residue was purified bypreparative HPLC (gradient 0.1% TFA in CH₃CN) to provide the titlecompound as light-yellow oil. MS (ESI, pos. ion.) m/z: 426 (M+1).

Example 31

2′-[(3-Pyrrolidin-1-yl-propylamino)-methyl]-biphenyl-4-carboxylic acidquinolin-7-ylamide. To a solution of 2′-formyl-biphenyl-4-carboxylicacid quinolin-7-ylamide, Example 28, (50 mg, 0.14 mmol),3-pyrrolidin-1-yl-propylamine (54 mg, 0.42 mmol, Aldrich) in DMF (1 mL)and MeOH (1 mL) was added glacial AcOH (1 drop), and the mixture wasstirred at 50° C. for 30 min. Sodium triacetoxyborohydride (136 mg, 0.64mmol) was added in small portions and the reaction mixture was stirredat 50° C. for 30 min. The reaction mixture was cooled to roomtemperature and concentrated in vacuo. The solid residue was dissolvedin EtOAc (60 mL) and washed with 0.5 N NaOH (10 mL). The EtOAc layer wasseparated, washed with brine, dried over MgSO₄, and filtered. Thefiltrate was evaporated in vacuo and the residue was purified by silicagel column chromatography (gradient, 5 to 10% (2 M NH₃ in MeOH) inCH₂Cl₂) to provide the title compound as light-yellow oil. MS (ESI, pos.ion.) m/z: 465 (M+1).

Example 32

(a) 6-Bromo-naphthalene-2-carbonyl chloride. This material was preparedanalogous to the procedure described for Example 1(a).6-Bromonaphthalene-2-carboxylic acid (924 mg, 3.68 mmol, Lancaster)reacted with oxalyl chloride (3.68 mL, 2 M solution in CH₂Cl₂, 7.36mmol, Aldrich) to give the title compound as a pale-yellow solid, whichwas used in the next step without purification.

(b) 6-Bromo-naphthalene-2-carboxylic acid quinolin-7-ylamide. Thismaterial was prepared analogous to the procedure described for Example1(c). 6-Bromo-naphthalene-2-carbonyl chloride, Example 32(a), (972 mg,3.6 mmol) reacted with 7-amino-quinoline (466 mg, 3.23 mmol, preparedaccording to the procedure described in WO03099284) to give the titlecompound as a brown solid. Mp 239.5-241.5° C. MS (ESI, pos. ion) m/z:378 (M+1).

Example 33

6-Morpholin-4-yl-naphthalene-2-carboxylic acid quinolin-7-ylamide. To asolution of 6-bromo-naphthalene-2-carboxylic acid quinolin-7-ylamide,Example 32(b), (40 mg, 0.106 mmol) in dioxane (2 mL) was addedtris(dibenzylideneacetone)dipalladium(0) (5 mg, Aldrich),biphenyl-2-yl-di-tert-butyl-phosphane (5 mg, Strem), morpholine (74 mg,0.85 mmol, Aldrich) and lithium bis(trimethylsilyl)amide (0.53 ml of 1 Msolution in THF, 0.53 mmol, Aldrich). The mixture was heated inmicrowave at 150° C. for 5 min, cooled to room temperature, andpartitioned between satd NH₄Cl (5 mL) and EtOAc (30 mL). The EtOAc layerwas separated, washed with brine, dried over MgSO₄, and filtered. Thefiltrate was evaporated in vacuo and the residue was purified by silicagel column chromatography (gradient, 5 to 10% (2 M NH₃ in MeOH) inCH₂Cl₂) to provide the title compound as a yellow amorphous solid. MS(ESI, pos. ion) m/z: 384 (M+1).

Example 34

6-(4-Isopropyl-piperazin-1-yl)-naphthalene-2-carboxylic acidquinolin-7-ylamide. This material was prepared analogous to theprocedure described for Example 33. 6-Bromo-naphthalene-2-carboxylicacid quinolin-7-ylamide, Example 32(b), (116 mg, 0.31 mmol) reacted with1-isopropylpiperazine (315 mg, 2.46 mmol, Aldrich) to give the titlecompound as a yellow amorphous solid. MS (ESI, pos. ion) m/z: 426 (M+1).

Example 35

6-Pyridin-3-yl-naphthalene-2-carboxylic acid quinolin-7-ylamide. Thismaterial was prepared analogous to the procedure described for Example 1(a). 6-Bromo-naphthalene-2-carboxylic acid quinolin-7-ylamide, Example32(b), (67 mg, 0.18 mmol) reacted with 3-pyridine boronic acid (24 mg,0.2 mmol, Fluorochem) to give the title compound as a brown amorphoussolid. MS (ESI, pos. ion) m/z: 376 (M+1).

Example 36

(a) 6-Bromo-quinoline-2-carboxylic acid methyl ester. A mixture of6-bromo-1,2,3,4-tetrahydro-quinoline-2-carboxylic acid methyl ester (197mg, 0.73 mmol, Astatech) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone(331 mg, 1.46 mmol, Aldrich) in toluene (5 mL) was stirred at roomtemperature for 30 min. The reaction mixture was evaporated in vacuo andthe residue was purified by silica gel column chromatography (gradient,25 to 60% EtOAc in hexane) to provide the title compound. MS (ESI, pos.ion) m/z: 267 (M+1).

(b) 6-Bromo-quinoline-2-carboxylic acid. A mixture of6-bromo-quinoline-2-carboxylic acid methyl ester, Example 36(a), (168mg, 0.63 mmol), LiOH (30 mg, 1.26 mmol), MeOH (2 mL) and water (2 mL)was heated at 80° C. for 30 min. The reaction mixture was cooled to roomtemperature, acidified with 1 N HCl and extracted with EtOAc (2×15 mL).The EtOAc extracts were combined, washed with brine, dried over MgSO₄,and filtered. The filtrate was evaporated in vacuo to give the titlecompound as a brown solid. MS (ESI, pos. ion) m/z: 253 (M+1).

(c) 6-Bromo-quinoline-2-carbonyl chloride hydrochloride. This materialwas prepared analogous to the procedure described for Example 1(a).6-Bromo-quinoline-2-carboxylic acid, Example 36(b), (113 mg, 0.45 mmol)reacted with oxalyl chloride (0.45 mL, 2 M solution in CH₂Cl₂, 0.9 mmol,Aldrich) to give the crude title compound, which was used in the nextstep without purification.

(d) 6-Bromo-quinoline-2-carboxylic acid quinolin-7-ylamide. Thismaterial was prepared analogous to the procedure described for Example1(c). 6-Bromo-quinoline-2-carbonyl chloride hydrochloride (the crudeproduct of Example 36(c), ˜0.45 mmol) reacted with 7-amino-quinoline (58mg, 0.4 mmol, prepared according to the procedure described inWO03099284) to give the title compound as a dark-purple solid. Mp156-157° C. MS (ESI, pos. ion) m/z: 379 (M+1).

Example 37

(a) 1-Isopropyl-2-trifluoromethyl-1H-benzoimidazole-5-carbonyl chloridehydrochloride. This material was prepared analogous to the proceduredescribed for Example 1 (a).1-Isopropyl-2-trifluoromethyl-1H-benzoimidazole-5-carboxylic acid (414mg, 1.52 mmol, Oakwood) reacted with oxalyl chloride (1.52 mL, 2 Msolution in CH₂Cl₂, 3.04 mmol, Aldrich) to give the crude titlecompound, which was used in the next step without purification.

(b) 1-Isopropyl-2-trifluoromethyl-1H-benzoimidazole-5-carboxylic acidquinolin-7-ylamide. This material was prepared analogous to theprocedure described for Example 1(c).1-Isopropyl-2-trifluoromethyl-1H-benzoimidazole-5-carbonyl chloridehydrochloride, Example 37(a), (355 mg, 1.22 mmol) reacted with7-amino-quinoline (151 mg, 1.05 mmol, prepared according to theprocedure described in WO03099284) to give the title compound as a whitefilm. MS (ESI, pos. ion) m/z: 399 (M+1).

Example 38

(a) 6-Trifluoromethyl-imidazo[1,2-a]pyridine-2-carboxylic acid ethylester. A mixture of 3-bromo-2-oxo-propionic acid ethyl ester (6.4 mL,50.9 mmol, Aldrich) and 5-trifluoromethyl-pyridin-2-ylamine (1.65 g,10.2 mmol, Maybridge) in EtOH (20 mL) was heated at 80° C. for 48 h, andleft at room temperature for 18 h. The white solid that precipitated wasfiltered, and the filter cake was rinsed with ether (10 mL), and driedin vacuo to provide the title compound. MS (ESI, pos. ion.) m/z: 258(M+1).

(b) 6-Trifluoromethyl-imidazo[1,2-a]pyridine-2-carbonyl chloridehydrochloride. This material was prepared analogous to the proceduresdescribed for Example 25(b) starting from6-trifluoromethyl-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester,Example 33(a), (65 mg, 0.25 mmol). The crude title compound was isolatedas an amorphous solid and used in the next step without purification.

(c) 6-Trifluoromethyl-imidazo[1,2-a]pyridine-2-carboxylic acidquinolin-7-ylamide. This material was prepared analogous to theprocedure described for Example 1(c).6-Trifluoromethyl-imidazo[1,2-a]pyridine-2-carbonyl chloridehydrochloride (the crude product of Example 38(b), ˜0.25 mmol) reactedwith 7-amino-quinoline (36 mg, 0.25 mmol, prepared according to theprocedure described in WO03099284) to give the title compound as ayellow amorphous solid. MS (ESI, pos. ion) m/z: 357 (M+1).

Additional Examples

Table 2. The following examples were prepared from 7-amino-quinoline,prepared according to the procedure described in WO030992841 andcommercially available carboxylic acids according to the proceduresdescribed for the preparation of Example 1(a-c). TABLE 2 The followingexamples were prepared from 7-amino-quinoline, prepared according to theprocedure described in WO030992841 and commercially available carboxylicacids according to the procedures described for the preparation ofExample 1(a-c). Ex. Structure Melt Point (° C.) M.S. (ESI) m/z 39

amorphous solid 333 (M + 1) 40

91.5-92.0 371 (M + 1) 41

  93-93.5 409 (M + 1) 42

65.0-65.5 375 (M + 1) 43

79-80 359 (M + 1) 44

88-89 341 (M + 1)

Example 45

(a) 2-Trichloromethyl-6-trifluoromethyl-1H-benzoimidazole. To a solutionof 4-trifluoromethyl-benzene-1,2-diamine (1.76 g, 10 mmol, Lancaster) inDCM (20 mL) was added methyl 2,2,2-trichloroacetimidate (1.94 g, 11mmol, Aldrich) and glacial acetic acid (3 mL) with stirring at roomtemperature. The reaction mixture was stirred at room temperature for 16h and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (35% EtOAc/hexane) to give the title compound as abrown solid. MS (ESI, pos. ion) m/z: 303 (M+1).

(b) 6-Trifluoromethyl-1H-benzoimidazole-2-carboxylic acid. To a solutionof 2-trichloromethyl-6-trifluoromethyl-1H-benzoimidazole, Example 45(a),(1.8 g, 5.9 mmol) in MeOH (10 mL) was added 1 N aqueous NaOH solution(10 mL) and the mixture was stirred at room temperature for 16 h. Mostof the MeOH in the reaction mixture was evaporated in vacuo. The residuewas acidified to pH 6 by addition of acetic acid, and concentrated tohalf volume under reduced pressure. The solid precipitate was filteredand dried in vacuo to give the title compound as a white solid. MS (ESI,pos. ion) m/z: 231 (M+1).

(c) 6-Trifluoromethyl-1H-benzoimidazole-2-carboxylic acidquinolin-7-ylamide. To a solution of6-trifluoromethyl-1H-benzoimidazole-2-carboxylic acid, Example 45(b),(0.8 g, 3.4 mmol) in DMF (5 mL) was addedN{(dimethylamino)(1H-1,2,3-triazolo[4,5-b]pyridin-1-yl)-methylene}-N-methylmethanaminiumhexafluorophosphate N-oxide (190 mg, 0.5 mmol, Perseptive Biosystem),1-hydroxy-7-azabenzotriazole (68 mg, 0.5 mmol, Perseptive Biosystem) andN,N-diisopropylethylamine (0.2 mL, 1 mmol, Aldrich), and the mixture wasstirred at room temperature for 10 min. 7-Aminoquinoline (58 mg, 0.4mmol, prepared according to the procedure described in WO03099284) wasthen added, and the reaction mixture was stirred at room temperature for15 h. The reaction mixture was diluted with EtOAc (40 mL), washedsuccessively with water (10 mL), 1 N NaOH (20 mL), and brine (20 mL),dried over MgSO₄, filtered, and concentrated in vacuo. The residue waspurified by silica gel column chromatography (60% EtOAc/hexane) to givethe title compound as a white solid. MS (ESI, pos. ion) m/z: 357 (M+1).

Example 46

1-(4-(Trifluoromethyl)benzyl)-6-bromo-N-(quinolin-7-yl)-1H-indole-2-carboxamide.This material was prepared analogous to the procedures described forExample 20, starting from 6-bromo-1H-indole-2-carboxylic acid ethylester (Asymchem) and using 4-(trifluoromethyl)benzyl chloride asalkylating agent. The title compound was isolated as an off-whiteamorphous solid. MS (ESI, pos. ion) m/z: 526 (M+1).

Capsaicin-Induced Ca2+ Influx in Primary Dorsal Root Ganglion Neurons

Embryonic 19 day old (E19) dorsal root ganglia (DRG) were dissected fromtimed-pregnant, terminally anesthetized Sprague-Dawley rats (CharlesRiver, Wilmington, Mass.) and collected in ice-cold L-15 media (LifeTechnologies, Grand Island, N.Y.) containing 5% heat inactivated horseserum (Life Technologies). The DRG were then dissociated into singlecell suspension using a papain dissociation system (WorthingtonBiochemical Corp., Freehold, N.J.). The dissociated cells were pelletedat 200×g for 5 min and re-suspended in EBSS containing 1 mg/ml ovomucoidinhibitor, 1 mg/ml ovalbumin and 0.005% DNase. Cell suspension wascentrifuged through a gradient solution containing 10 mg/ml ovomucoidinhibitor, 10 mg/ml ovalbumin at 200×g for 6 min to remove cell debris;and filtered through a 88-μm nylon mesh (Fisher Scientific, Pittsburgh,Pa.) to remove any clumps. Cell number was determined with ahemocytometer and cells were seeded into poly-ornithine 100 μg/ml(Sigma) and mouse laminin 1 μg/ml (Life Technologies)-coated 96-wellplates at 10×10³ cells/well in complete medium. The complete mediumconsists of minimal essential medium (MEM) and Ham's F12, 1:1,penicillin (100 U/ml), and streptomycin (100 μg/ml), and nerve growthfactor (10 ng/ml), 10% heat inactivated horse serum (Life Technologies).The cultures were kept at 37° C., 5% CO₂ and 100% humidity.

For controlling the growth of non-neuronal cells,5-fluoro-2′-deoxyuridine (75 μM) and uridine (180 μM) were included inthe medium. Activation of VR1 is achieved in these cellular assays usingeither a capsaicin stimulus (ranging from 0.01-10 μM) or by an acidstimulus (addition of 30 mM Hepes/Mes buffered at pH 4.1). Compounds arealso tested in an assay format to evaluate their agonist properties atVR1.

Capsaicin Antagonist Assay: E-19 DRG cells at 5 days in culture areincubated with serial concentrations of VR1 antagonists, in HBSS (Hanksbuffered saline solution supplemented with BSA 0.1 mg/ml and 1 mM Hepesat pH 7.4) for 15 min, 37° C. Cells are then challenged with a VR1agonist, capsaicin 200 nM, in activation buffer containing 0.1 mg/mlBSA, 15 mM Hepes, pH 7.4, and 10 μCi/ml ⁴⁵Ca²⁺ (Amersham) in Ham's F12for 2 min at 37° C.

Acid Antagonist Assay: Compounds are pre-incubated with E-19 DRG cellsfor 2 minutes prior to addition of Calcium-45 in 30 mM Hepes/Mes buffer(Final Assay pH 5) and then left for an additional 2 minutes prior tocompound washout. Final 45Ca (Amersham CES3-2mCi) at 10 μCi/mL.

Agonist Assay: Compounds are incubated with E-19 DRG cells for 2 minutesin the presence of Calcium-45 prior to compound washout. Final ⁴⁵Ca²⁺(Amersham CES3-2mCi) at 10 μCi/mL.

Compound Washout and Analysis: Assay plates are washed using an ELX405plate washer (Bio-Tek Instruments Inc.) immediately after functionalassay. Wash 3× with PBS Mg2+/Ca2+ free, 0.1 mg/mL BSA. Aspirate betweenwashes. Read plates using a MicroBeta Jet (Wallac Inc.). Compoundactivity is then calculated using appropriate computational algorithms.

⁴⁵Calcium²⁺ Assay Protocol

Compounds may be assayed using Chinese Hamster Ovary cell lines stablyexpressing either human VR1 or rat VR1 under a CMV promoter. Cells canbe cultured in Growth Medium, routinely passaged at 70% confluency usingtrypsin and plated in the assay plate 24 hours prior to compoundevaluation.

Possible Growth Medium:

-   -   DMEM, high glucose (Gibco 11965-084).    -   10% Dialyzed serum (Hyclone SH30079.03).    -   1× Non-Essential Amino Acids (Gibco 11140-050).    -   1× Glutamine-Pen-Strep (Gibco 10378-016).    -   Geneticin, 450 μg/mL (Gibco 10131-035).

Compounds can be diluted in 100% DMSO and tested for activity overseveral log units of concentration [40 μM-2 pM]. Compounds may befurther diluted in HBSS buffer (pH 7.4) 0.1 mg/mL BSA, prior toevaluation. Final DMSO concentration in assay would be 0.5%. Each assayplate can be controlled with a buffer only and a known antagonistcompound (either capsazepine or one of the described VR1 antagonists).

Activation of VR1 can be achieved in these cellular assays using eithera capsaicin stimulus (ranging from 0.1-1 μM) or by an acid stimulus(addition of 30 mM Hepes/Mes buffered at pH 4.1). Compounds may alsotested in an assay format to evaluate their agonist properties at VR1.

Capsaicin Antagonist Assay: Compounds may be pre-incubated with cells(expressing either human or rat VR1) for 2 minutes prior to addition ofCalcium-45 and Capsaicin and then left for an additional 2 minutes priorto compound washout. Capsaicin (0.5 nM) can be added in HAM's F12, 0.1mg/mL BSA, 15 mM Hepes at pH 7.4. Final ⁴⁵Ca (Amersham CES3-2mCi) at 10μCi/mL.

Acid Antagonist Assay: Compounds can be pre-incubated with cells(expressing either human or rat VR1) for 2 minutes prior to addition ofCalcium-45 in 30 mM Hepes/Mes buffer (Final Assay pH 5) and then leftfor an additional 2 minutes prior to compound washout. Final ⁴⁵Ca(Amersham CES3-2mCi) at 10 μCi/mL.

Agonist Assay: Compounds can be incubated with cells (expressing eitherhuman or rat VR1) for 2 minutes in the presence of Calcium-45 prior tocompound washout. Final ⁴⁵Ca (Amersham CES3-2mCi) at 10 μCi/mL.

Compound Washout and Analysis: Assay plates can be washed using anELX405 plate washer (Bio-Tek Instruments Inc.) immediately afterfunctional assay. One can wash 3× with PBS Mg2⁺/Ca²⁺ free, 0.1 mg/mLBSA, aspirating between washes. Plates may be read using a MicroBeta Jet(Wallac Inc.). Compound activity may then calculated using appropriatecomputational algorithms.

Useful nucleic acid sequences and proteins may be found in U.S. Pat.Nos. 6,335,180, 6, 406,908 and 6,239,267, herein incorporated byreference in their entirety.

For the treatment of vanilloid-receptor-diseases, such as acute,inflammatory and neuropathic pain, dental pain, general headache,migraine, cluster headache, mixed-vascular and non-vascular syndromes,tension headache, general inflammation, arthritis, rheumatic diseases,osteoarthritis, inflammatory bowel disorders, inflammatory eyedisorders, inflammatory or unstable bladder disorders, psoriasis, skincomplaints with inflammatory components, chronic inflammatoryconditions, inflammatory pain and associated hyperalgesia and allodynia,neuropathic pain and associated hyperalgesia and allodynia, diabeticneuropathy pain, causalgia, sympathetically maintained pain,deafferentation syndromes, asthma, epithelial tissue damage ordysfunction, herpes simplex, disturbances of visceral motility atrespiratory, genitourinary, gastrointestinal or vascular regions,wounds, burns, allergic skin reactions, pruritus, vitiligo, generalgastrointestinal disorders, gastric ulceration, duodenal ulcers,diarrhea, gastric lesions induced by necrotising agents, hair growth,vasomotor or allergic rhinitis, bronchial disorders or bladderdisorders, the compounds of the present invention may be administeredorally, parentally, by inhalation spray, rectally, or topically indosage unit formulations containing conventional pharmaceuticallyacceptable carriers, adjuvants, and vehicles. The term parenteral asused herein includes, subcutaneous, intravenous, intramuscular,intrasternal, infusion techniques or intraperitoneally.

Treatment of diseases and disorders herein is intended to also includethe prophylactic administration of a compound of the invention, apharmaceutical salt thereof, or a pharmaceutical composition of eitherto a subject (i.e., an animal, preferably a mammal, most preferably ahuman) believed to be in need of preventative treatment, such as, forexample, pain, inflammation and the like.

The dosage regimen for treating vanilloid-receptor-mediated diseases,cancer, and/or hyperglycemia with the compounds of this invention and/orcompositions of this invention is based on a variety of factors,including the type of disease, the age, weight, sex, medical conditionof the patient, the severity of the condition, the route ofadministration, and the particular compound employed. Thus, the dosageregimen may vary widely, but can be determined routinely using standardmethods. Dosage levels of the order from about 0.01 mg to 30 mg perkilogram of body weight per day, preferably from about 0.1 mg to 10mg/kg, more preferably from about 0.25 mg to 1 mg/kg are useful for allmethods of use disclosed herein.

The pharmaceutically active compounds of this invention can be processedin accordance with conventional methods of pharmacy to produce medicinalagents for administration to patients, including humans and othermammals.

For oral administration, the pharmaceutical composition may be in theform of, for example, a capsule, a tablet, a suspension, or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a given amount of the active ingredient. For example,these may contain an amount of active ingredient from about 1 to 2000mg, preferably from about 1 to 500 mg, more preferably from about 5 to150 mg. A suitable daily dose for a human or other mammal may varywidely depending on the condition of the patient and other factors, but,once again, can be determined using routine methods.

The active ingredient may also be administered by injection as acomposition with suitable carriers including saline, dextrose, or water.The daily parenteral dosage regimen will be from about 0.1 to about 30mg/kg of total body weight, preferably from about 0.1 to about 10 mg/kg,and more preferably from about 0.25 mg to 1 mg/kg.

Injectable preparations, such as sterile injectable aqueous oroleaginous suspensions, may be formulated according to the known areusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a non-toxic parenterally acceptable diluent or solvent,for example as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed, including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable non-irritating excipient such as cocoabutter and polyethylene glycols that are solid at ordinary temperaturesbut liquid at the rectal temperature and will therefore melt in therectum and release the drug.

A suitable topical dose of active ingredient of a compound of theinvention is 0.1 mg to 150 mg administered one to four, preferably oneor two times daily. For topical administration, the active ingredientmay comprise from 0.001% to 10% w/w, e.g., from 1% to 2% by weight ofthe formulation, although it may comprise as much as 10% w/w, butpreferably not more than 5% w/w, and more preferably from 0.1% to 1% ofthe formulation.

Formulations suitable for topical administration include liquid orsemi-liquid preparations suitable for penetration through the skin(e.g., liniments, lotions, ointments, creams, or pastes) and dropssuitable for administration to the eye, ear, or nose.

For administration, the compounds of this invention are ordinarilycombined with one or more adjuvants appropriate for the indicated routeof administration. The compounds may be admixed with lactose, sucrose,starch powder, cellulose esters of alkanoic acids, stearic acid, talc,magnesium stearate, magnesium oxide, sodium and calcium salts ofphosphoric and sulfuric acids, acacia, gelatin, sodium alginate,polyvinyl-pyrrolidine, and/or polyvinyl alcohol, and tableted orencapsulated for conventional administration. Alternatively, thecompounds of this invention may be dissolved in saline, water,polyethylene glycol, propylene glycol, ethanol, corn oil, peanut oil,cottonseed oil, sesame oil, tragacanth gum, and/or various buffers.Other adjuvants and modes of administration are well known in thepharmaceutical art. The carrier or diluent may include time delaymaterial, such as glyceryl monostearate or glyceryl distearate alone orwith a wax, or other materials well known in the art.

The pharmaceutical compositions may be made up in a solid form(including granules, powders or suppositories) or in a liquid form(e.g., solutions, suspensions, or emulsions). The pharmaceuticalcompositions may be subjected to conventional pharmaceutical operationssuch as sterilization and/or may contain conventional adjuvants, such aspreservatives, stabilizers, wetting agents, emulsifiers, buffers etc.

Solid dosage forms for oral administration may include capsules,tablets, pills, powders, and granules. In such solid dosage forms, theactive compound may be admixed with at least one inert diluent such assucrose, lactose, or starch. Such dosage forms may also comprise, as innormal practice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets, and pills, the dosage forms may also comprise buffering agents.Tablets and pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration may include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water. Suchcompositions may also comprise adjuvants, such as wetting, sweetening,flavoring, and perfuming agents.

Compounds of the present invention can possess one or more asymmetriccarbon atoms and are thus capable of existing in the form of opticalisomers as well as in the form of racemic or non-racemic mixturesthereof. The optical isomers can be obtained by resolution of theracemic mixtures according to conventional processes, e.g., by formationof diastereoisomeric salts, by treatment with an optically active acidor base. Examples of appropriate acids are tartaric, diacetyltartaric,dibenzoyltartaric, ditoluoyltartaric, and camphorsulfonic acid and thenseparation of the mixture of diastereoisomers by crystallizationfollowed by liberation of the optically active bases from these salts. Adifferent process for separation of optical isomers involves the use ofa chiral chromatography column optimally chosen to maximize theseparation of the enantiomers. Still another available method involvessynthesis of covalent diastereoisomeric molecules by reacting compoundsof the invention with an optically pure acid in an activated form or anoptically pure isocyanate. The synthesized diastereoisomers can beseparated by conventional means such as chromatography, distillation,crystallization or sublimation, and then hydrolyzed to deliver theenantiomerically pure compound. The optically active compounds of theinvention can likewise be obtained by using active starting materials.These isomers may be in the form of a free acid, a free base, an esteror a salt.

Likewise, the compounds of this invention may exist as isomers, that iscompounds of the same molecular formula but in which the atoms, relativeto one another, are arranged differently. In particular, the alkylenesubstituents of the compounds of this invention, are normally andpreferably arranged and inserted into the molecules as indicated in thedefinitions for each of these groups, being read from left to right.However, in certain cases, one skilled in the art will appreciate thatit is possible to prepare compounds of this invention in which thesesubstituents are reversed in orientation relative to the other atoms inthe molecule. That is, the substituent to be inserted may be the same asthat noted above except that it is inserted into the molecule in thereverse orientation. One skilled in the art will appreciate that theseisomeric forms of the compounds of this invention are to be construed asencompassed within the scope of the present invention.

The compounds of the present invention can be used in the form of saltsderived from inorganic or organic acids. The salts include, but are notlimited to, the following: acetate, adipate, alginate, citrate,aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate,ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate,heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methansulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate,pectinate, persulfate, 2-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate, mesylate, andundecanoate. Also, the basic nitrogen-containing groups can bequaternized with such agents as lower alkyl halides, such as methyl,ethyl, propyl, and butyl chloride, bromides and iodides; dialkylsulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, longchain halides such as decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides, aralkyl halides like benzyl and phenethylbromides, and others. Water or oil-soluble or dispersible products arethereby obtained.

Examples of acids that may be employed to from pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, sulfuric acid and phosphoric acid and such organicacids as oxalic acid, maleic acid, succinic acid and citric acid. Otherexamples include salts with alkali metals or alkaline earth metals, suchas sodium, potassium, calcium or magnesium or with organic bases.

Also encompassed in the scope of the present invention arepharmaceutically acceptable esters of a carboxylic acid or hydroxylcontaining group, including a metabolically labile ester or a prodrugform of a compound of this invention. A metabolically labile ester isone which may produce, for example, an increase in blood levels andprolong the efficacy of the corresponding non-esterified form of thecompound. A prodrug form is one which is not in an active form of themolecule as administered but which becomes therapeutically active aftersome in vivo activity or biotransformation, such as metabolism, forexample, enzymatic or hydrolytic cleavage. For a general discussion ofprodrugs involving esters see Svensson and Tunek Drug Metabolism Reviews165 (1988) and Bundgaard Design of Prodrugs, Elsevier (1985). Examplesof a masked carboxylate anion include a variety of esters, such as alkyl(for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl),aralkyl (for example, benzyl, p-methoxybenzyl), andalkylcarbonyloxyalkyl (for example, pivaloyloxymethyl). Amines have beenmasked as arylcarbonyloxymethyl substituted derivatives which arecleaved by esterases in vivo releasing the free drug and formaldehyde(Bungaard J. Med. Chem. 2503 (1989)). Also, drugs containing an acidicNH group, such as imidazole, imide, indole and the like, have beenmasked with N-acyloxymethyl groups (Bundgaard Design of Prodrugs,Elsevier (1985)). Hydroxy groups have been masked as esters and ethers.EP 039,051 (Sloan and Little, Apr. 11, 1981) discloses Mannich-basehydroxamic acid prodrugs, their preparation and use. Esters of acompound of this invention may include, for example, the methyl, ethyl,propyl, and butyl esters, as well as other suitable esters formedbetween an acidic moiety and a hydroxyl containing moiety. Metabolicallylabile esters, may include, for example, methoxymethyl, ethoxymethyl,iso-propoxymethyl, α-methoxyethyl, groups such asα-((C₁-C₄)alkyloxy)ethyl, for example, methoxyethyl, ethoxyethyl,propoxyethyl, iso-propoxyethyl, etc.; 2-oxo-1,3-dioxolen-4-ylmethylgroups, such as 5-methyl-2-oxo-1,3,dioxolen-4-ylmethyl, etc.; C₁-C₃alkylthiomethyl groups, for example, methylthiomethyl, ethylthiomethyl,isopropylthiomethyl, etc.; acyloxymethyl groups, for example,pivaloyloxymethyl, α-acetoxymethyl, etc.; ethoxycarbonyl-1-methyl; orα-acyloxy-α-substituted methyl groups, for example α-acetoxyethyl.

Further, the compounds of the invention may exist as crystalline solidswhich can be crystallized from common solvents such as ethanol,N,N-dimethylformamide, water, or the like. Thus, crystalline forms ofthe compounds of the invention may exist as polymorphs, solvates and/orhydrates of the parent compounds or their pharmaceutically acceptablesalts. All of such forms likewise are to be construed as falling withinthe scope of the invention.

While the compounds of the invention can be administered as the soleactive pharmaceutical agent, they can also be used in combination withone or more compounds of the invention or other agents. Whenadministered as a combination, the therapeutic agents can be formulatedas separate compositions that are given at the same time or differenttimes, or the therapeutic agents can be given as a single composition.

The foregoing is merely illustrative of the invention and is notintended to limit the invention to the disclosed compounds. Variationsand changes, which are obvious to one skilled in the art, are intendedto be within the scope and nature of the invention, which are defined,in the appended claims.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

1. A compound having the formula,

or a pharmaceutically acceptable salt or solvate thereof, wherein, P isselected from phenyl, heteroaryl or heterocyclyl; R¹ and R² areindependently selected from halo, alkyl, alkoxy, cycloalkyl, aralkyl,aralkoxy, cycloalkylalkyl, cycloalkylalkoxy, —CN, —NO₂, —OH, ═O, —OCF₃,—CF₃, NR⁴R⁵, —S(O)_(m)R⁶, —S(O)₂NR⁴R⁵, —OS(O)₂R⁶, —OS(O)₂CF₃,—O(CH₂)_(n)NR⁴R⁵, —C(O)CF₃, —C(O)alkyl, —C(O)cycloalkyl, —C(O)aralkyl,—C(O)Ar, —C(O)(CH₂)_(n)OR⁶, C(O)(CH₂)_(n)NR⁴R⁵, —C(O)alkoxy, —C(O)NR⁴R⁵,—(CH₂)_(n)C(O)alkoxy, (CH₂)_(n)OC(O)R⁶, —O(CH₂)_(n)OR⁶, —(CH₂)_(n)OR⁶,—(CH₂)_(n)NR⁴R⁵, (CH₂)_(n)C(O)NR⁴R⁵, —(CH₂)_(n)N(R⁴)C(O)R⁶,—(CH₂)_(n)S(O)₂NR⁴R⁵, (CH₂)_(n)N(R⁴)S(O)₂R⁶, -ZAr, —(CH₂)_(n)S(O)₂R⁶,—(OCH₂)_(n)S(O)₂R⁶, N(R⁴)S(O)₂R⁶, —N(R⁴)C(O)R⁶, —(CH₂)_(n)N(R⁴)S(O)₂R⁶,—(CH₂)_(n)N(R⁴)C(O)R⁶ or —(CH₂)_(n)C(O)alkyl; R³ is selected from alkyl,alkoxy, —CF₃, halo, —O(CH₂)_(n)OR⁶, —O(CH₂)_(n)NR⁴R⁵, phenyl,cyclohexyl, benzo[1,3]dioxolyl, morpholinyl, pyridyl, pyrimidinyl,pyrazinyl, piperazinyl, piperidinyl, pyridizinyl, thienyl, furyl,pyrazolyl, pyrrolyl, triazolyl, indanyl, imidazolyl, oxazolyl,thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl or thiadiazolyl;wherein said alkyl, alkoxy, phenyl, cyclohexyl, benzo[1,3]dioxolyl,morpholinyl, pyridyl, pyrimidinyl, pyrazinyl, piperazinyl, piperidinyl,pyridizinyl, thienyl, furyl, pyrazolyl, pyrrolyl, triazolyl, indanyl,imidazolyl, oxazolyl, thiazolyl, oxediazolyl, isothiazolyl, isoxazolyland thiadiazolyl groups may be optionally substituted by one or moregroups, which may be the same or different, selected from R²; R⁴ and R⁵may be the same or different and represent —H or alkyl or R⁴ and R⁵together with the nitrogen atom to which they are attached form aheterocyclic ring; R⁶ is —H, alkyl or aryl; R⁷ is —H, alkyl or aryl; R⁸is selected from H, alkyl, hydroxyalkyl, cycloalkyl, aralkyl,alkoxyalkyl, cycloalkylalkyl, heterocyclylalkyl, —S(O)_(m)R⁶, —C(O)CF₃,—C(O)alkyl, —C(O)cycloalkyl, —C(O)aralkyl, —C(O)Ar, —C(O)(CH₂)_(n)OR⁶,—C(O)(CH₂)_(n)NR⁴R⁵, C(O)alkoxy, —C(O)NR⁴R⁵, —(CH₂)_(n)C(O)alkoxy,—(CH₂)_(n)OC(O)R⁶, —(CH₂)_(n)OR⁶, —(CH₂)_(n)NR⁴R⁵, —(CH₂)_(n)C(O)NR⁴R⁵,—(CH₂)_(n)N(R⁴)C(O)R⁶, —(CH₂)_(n)S(O)₂NR⁴R⁵, —(CH₂)_(n)N(R⁴)S(O)₂R⁶,—(CH₂)_(n)S(O)₂R⁶, —(CH₂)_(n)N(R⁴)S(O)₂R⁶, —(CH₂)_(n)N(R⁴)C(O)R⁶ or—(CH₂)_(n)C(O)alkyl; or where X is NR⁸ and Y is C(R⁹)₂, R⁸ may combinewith R¹ to form a benzoquinuclidine group; R⁹ is H or R¹; Ar is aryl orheteroaryl, each of which may be optionally substituted by R². Z is abond, O, S, NR⁷ or CH₂; m is 0, 1 or 2; n is an integer value from 1 to6; q and r are independently selected from 0, 1, 2 or 3; s is 0, 1, 2 or3; and X and Y are selected from the following combinations: X Y N CR⁹NR⁸ C(R⁹)₂ CR⁹ N C(R⁹)₂ NR⁸

with the proviso that said compound of formula (I) is not a compoundselected from:N-{3-[(N,N-Dimethylamino)methyl]-1,2,3,4-tetrahydro-7-guinolinyl}-4biphenylcarboxamide;N-{3-[(N,N-Dimethylamino)methyl]-1-formyl-1,2,3,4-tetrahydro-7-quinolinyl}-4-biphenylcarboxamide;N-{1-Acetyl-3-[(N,N-dimethylamino)methyl]-1,2,3,4-tetrahydro-7-quinolinyl}-4biphenylcarboxamide;N-{3-[(N,N-Dimethylamino)methyl]-1-methylsulfonyl-1,2,3,4-tetrahydro-7quinolinyl}-4-biphenylcarboxamide;5-amino-N-isoquinolin-5-yl-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3carboxamide;5-methyl-N-quinolin-8-yl-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3carboxamide;5-methyl-N-quinolin-7-yl-1-[3-trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide;5-methyl-N-quinolin-3-yl-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide;N-isoquinolin-5-yl-5-methyl-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide;5-methyl-N-quinolin-5-yl-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide;1-(3-chlorophenyl)-N-isoquinolin-5-yl-5-methyl-1H-pyrazole-3-carboxamide;N-isoquinolin-5-yl-1-(3-methoxyphenyl)-5-methyl-1H-pyrazole-3-carboxamide;1-(3-fluorophenyl)-N-isoquinolin-5-yl-5-methyl-1H-pyrazole-3-carboxamide;1-(2-chloro-5-trifluoromethylphenyl)-N-isoquinolin-5-yl-5-methyl-1H-pyrazole-3carboxamide;5-methyl-N-(3-methylisoquinolin-5-yl)-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide;and5-methyl-N-(1,2,3,4-tetrahydroisoquinolin-5-yl)-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide.2. A compound according to claim 1, having the formula

or a pharmaceutically acceptable salt or solvate thereof, wherein, P isselected from phenyl, heteroaryl or heterocyclyl; R¹ and R² areindependently selected from halo, alkyl, alkoxy, cycloalkyl, aralkyl,aralkoxy, cycloalkylalkyl, cycloalkylalkoxy, —CN, —NO₂, —OH, ═O, —OCF₃,—CF₃, NR⁴R⁵, —S(O)_(m)R⁶, —S(O)₂NR⁴R⁵, —OS(O)₂R⁶, —OS(O)₂CF₃,—O(CH₂)_(n)NR⁴R⁵, —C(O)CF₃, —C(O)alkyl, —C(O)cycloalkyl, —C(O)aralkyl,—C(O)Ar, —C(O)(CH₂)_(n)OR⁶, C(O)(CH₂)_(n)NR⁴R⁵, —C(O)alkoxy, —C(O)NR⁴R⁵,—(CH₂)_(n)C(O)alkoxy, (CH₂)_(n)OC(O)R⁶, —O(CH₂)_(n)OR⁶, —(CH₂)_(n)OR⁶,—(CH₂)_(n)NR⁴R⁵, (CH₂)_(n)C(O)NR⁴R⁵, —(CH₂)_(n)N(R⁴)C(O)R⁶,—(CH₂)_(n)S(O)₂NR⁴R⁵, (CH₂)_(n)N(R⁴)S(O)₂R⁶, -ZAr, —(CH₂)_(n)S(O)₂R⁶,(OCH₂)_(n)S(O)₂R⁶, N(R⁴)S(O)₂R⁶, —N(R⁴)C(O)R⁶, —(CH₂)_(n)N(R⁴)S(O)₂R⁶,—(CH₂)_(n)N(R⁴)C(O)R⁶ or (CH₂)_(n)C(O)alkyl; R³ is selected from alkyl,—CF₃, halo, phenyl, cyclohexyl, benzo[1,3]dioxolyl morpholinyl, pyridyl,pyrimidinyl, pyrazinyl, piperazinyl piperidinyl, pyridizinyl, thienyl,furyl, pyrazolyl, pyrrolyl, triazolyl, indanyl, imidazolyl, oxazolyl,thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl or thiadiazolyl;wherein said alkyl, alkoxy, phenyl, cyclohexyl, benzo[1,3]dioxolyl,morpholinyl, pyridyl, pyrimidinyl, pyrazinyl, piperazinyl, piperidinyl,pyridizinyl, thienyl, furyl, pyrazolyl, pyrrolyl, triazolyl, indanyl,imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyland thiadiazolyl groups may be optionally substituted by one or moregroups, which may be the same or different, selected from R²; R⁴ and R⁵may be the same or different and represent —H or alkyl or R⁴ and R⁵together with the nitrogen atom to which they are attached form aheterocyclic ring; R⁶ is H, alkyl or aryl; R⁷ is —H, alkyl or aryl; R⁸is selected from —H, alkyl, hydroxyalkyl, cycloalkyl, aralkyl,alkoxyalkyl, cycloalkylalkyl, heterocyclylalkyl, —S(O)R⁶, —C(O)CF₃,—C(O)alkyl, C(O)cycloalkyl, —C(O)aralkyl, —C(O)Ar, —C(O)(CH₂)_(n)OR⁶,—C(O)(CH₂)_(n)NR⁴R⁵, C(O)alkoxy, —C(O)NR⁴R⁵, —(CH₂)_(n)C(O)alkoxy,—(CH₂)_(n)OC(O)R⁶, —(CH₂)_(n)OR⁶, (CH₂)_(n)NR⁴R⁵, —(CH₂)_(n)C(O)NR⁴R⁵,—(CH₂)_(n)N(R⁴)C(O)R⁶, —(CH₂)_(n)S(O)₂NR⁴R⁵, —(CH₂)_(n)N(R⁴)S(O)₂R⁶,—(CH₂)_(n)S(O)₂R⁶, —(CH₂)_(n)N(R⁴)S(O)₂R⁶, —(CH₂)_(n)N(R⁴)C(O)R⁶ or—(CH₂)_(n)C(O)alkyl; or where X is NR⁸ and Y is C(R⁹)₂, R⁸ may combinewith R¹ to form a benzoquinuclidine group; R⁹ is —H or R¹; Ar is aryl orheteroaryl, each of which may be optionally substituted by R²; Z is abond, O, S, NR⁷ or CH₂; m is 0, 1 or 2; n is an integer value from 1 to6; q and r are independently selected from 0, 1, 2 or 3; s is 0, 1, 2 or3; and X is C(R⁹)₂ and Y is NR⁸ or X is NR⁸ and Y is C(R⁹)2; with theproviso that said compound is not a compound selected from:N-{3-[(N,N-Dimethylamino)methyl]-1,2,3,4-tetrahydro-7-quinolinyl}-4biphenylcarboxamide;N-{3-[(N,N-Dimethylamino)methyl]-1-formyl-1,2,3,4-tetrahydro-7-quinolinyl}-4biphenylcarboxamide;N-{1-Acetyl-3-[(N,N-dimethylamino)methyl]-1,2,3,4-tetrahydro-7-quinolinyl}-4biphenylcarboxamide;N-{3-(N,N-Dimethylamino)methyl]-1-methylsulfonyl-1,2,3,4-tetrahydro-7-quinolinyl}-4-biphenylcarboxamide;and5-methyl-N-(1,2,3,4-tetrahydroisoquinolin-5-yl)-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide.3. A compound according to claim 1 having the formula

or a pharmaceutically acceptable salt or solvate thereof, wherein, P isselected from phenyl, heteroaryl or heterocyclyl; R¹ and R² areindependently selected from halo, alkyl, alkoxy, cycloalkyl, aralkyl,aralkoxy, cycloalkylalkyl, cycloalkylalkoxy, —CN, —NO₂, —OH, —OCF₃,—CF₃, —NR⁴R⁵, —S(O)_(m)R⁶, —S(O)₂NR⁴R⁵, —OS(O)₂R⁶, —OS(O)₂CF₃,—O(CH₂)_(n)NR⁴R⁵, —C(O)CF₃, —C(O)alkyl, —C(O)cycloalkyl, —C(O)aralkyl,—C(O)Ar, —C(O)(CH₂)_(n)OR⁶, —C(O)(CH₂)_(n)NR⁴R⁵′, —C(O)alkoxy,—C(O)NR⁴R⁵′, —(CH₂)_(n)C(O)alkoxy, (CH₂)_(n)OC(O)R⁶, —(CH₂)_(n)OR⁶,—(CH₂)_(n)NR⁴R⁵, —(CH₂)_(n)C(O)NR⁴R⁵, —(CH₂)_(n)N(R⁴)C(O)R⁶,—(CH₂)_(n)S(O)₂NR⁴R⁵, —(CH₂)_(n)N(R⁴)S(O)₂R⁶, -ZAr, —(CH₂)_(n)S(O)₂R⁶,—(OCH₂)_(n)S(O)₂R⁶, —N(R⁴)S(O)₂R⁶, —N(R⁴)C(O)R⁶, —(CH₂)_(n)N(R⁴)S(O)₂R⁶,—(CH₂)_(n)N(R⁴)C(O)R⁶ or —(CH₂)_(n)C(O)alkyl; R³ is selected from halo,—CF₃, alkyl, alkoxy, —O(CH₂)_(n)OR⁶, —O(CH₂)_(n)NR⁴R⁵, phenyl,cyclohexyl, benzo[1,3]dioxolyl, morpholinyl, pyridyl, pyrimidinyl,pyrazinyl, piperazinyl, piperidinyl, pyridizinyl, thienyl, furyl,pyrazolyl, pyrrolyl, triazolyl, imidazolyl, oxazolyl, thiazolyl,oxadiazolyl, isothiazolyl, isoxazolyl or thiadiazolyl; which alkyl,alkoxy, phenyl, cyclohexyl, benzo[1,3]dioxolyl, morpholinyl, pyridyl,pyrimidinyl, pyrazinyl, piperazinyl, piperidinyl, pyridizinyl, thienyl,furyl, pyrazolyl, pyrrolyl, triazolyl, imidazolyl, oxazolyl, thiazolyl,oxediazolyl, isothiazolyl, isoxazolyl and thiadiazolyl groups may beoptionally substituted by one or more groups, which may be the same ordifferent, selected from R²; R⁴ and R⁵ may be the same or different andrepresent H or alkyl or R⁴ and R⁵ together with the nitrogen atom towhich they are attached form a heterocyclic ring; R⁶ is H, alkyl oraryl; R⁷ is H, alkyl or aryl; Ar is aryl or heteroaryl; each of whichmay be optionally substituted by R²; X and Y are selected from CR⁹ and Nwith the proviso that X and Y may not be the same; Z is a bond, O, S,NR⁷ or CH₂; m is 0, 1 or 2; n is an integer value from 1 to 6; q and rare independently selected from 0, 1, 2 or 3; and s is 0, 1, or 3; withthe proviso that said compound is not a compound selected from:5-amino-N-isoquinolin-5-yl-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3carboxamide;5-methyl-N-quinolin-8-yl-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3carboxamide;5-methyl-N-quinolin-7-yl-1-[3-trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide;5-methyl-N-quinolin-3-yl-1-[3-(trifluoromethyl)phenyl]-1H—pyrazole-3-carboxamide;N-isoquinolin-5-yl-5-methyl-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3carboxamide;5-methyl-N-quinolin-5-yl-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3carboxamide;1-(3-chlorophenyl)-N-isoquinolin-5-yl-5-methyl-1H-pyrazole-3-carboxamide;N-isoquinolin-5-yl-1-(3-methoxyphenyl)-5-methyl-1H-pyrazole-3-carboxamide;1-(3-fuorophenyl)-N-isoquinolin-5-yl-5-methyl-1H-pyrazole-3-carboxamide;1-(2-chloro-5-trifluoromethylphenyl)-N-isoquinolin-5-yl-5-methyl-1H-pyrazole-3carboxamide;5-methyl-N-(3-methylisoquinolin-5-yl)-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3carboxamide; andN-[3-[2-(diethylamino)ethyl]-1,2-dihydro-4-methyl-2-oxo-7-quinolinyl]-4-phenyl-1-piperazinecarboxamide.4. A compound according to claim 1 for use as an active therapeuticsubstance.
 5. A method for the treatment or prophylaxis of disorders inwhich antagonism of the VR1 receptor is beneficial in mammals, whichmethod comprises administering to a mammal in need thereof atherapeutically effective amount of a compound according to claim
 1. 6.Use of a compound according to claim 1, in the manufacture of amedicament for the treatment or prophylaxis of disorders in whichantagonism of the Vanillold (VR¹) receptor is beneficial.
 7. Apharmaceutical composition, which comprises a compound according toclaim 1, and a pharmaceutically acceptable carrier or excipienttherefor.
 8. A compound having the formula,

or a pharmaceutically acceptable salt or solvate thereof, wherein, J is═O, ═S, ═CHNO₂, ═N—CN, ═CHSO₂R^(b), ═NSO₂R^(b) or ═NHR^(b); P isselected from phenyl, heteroaryl or heterocyclyl; R¹ and R² areindependently selected from halo, alkyl, alkoxy, cycloalkyl, aralkyl,aralkoxy, cycloalkylalkyl, cycloalkylalkoxy, —CN, —NO₂, —OH, ═O, —OCF₃,—CF₃, NR⁴R⁵, —S(O)_(m)R⁶, —S(O)₂NR⁴R⁵, —OS(O)₂R⁶, —OS(O)₂CF₃,—O(CH₂)_(n)NR⁴R⁵, —C(O)CF₃, —C(O)H, —C(O)alkyl, —C(O)cycloalkyl,—C(O)aralkyl, —C(O)Ar, —C(O)(CH₂)_(n)OR⁶, C(O)(CH₂)_(n)NR⁴R⁵,—C(O)alkoxy, —C(O)NR⁴R⁵, —(CH₂)_(n)C(O)alkoxy, (CH₂)_(n)OC(O)R⁶,—O(CH₂)_(n)OR⁶, —(CH₂)_(n)NR⁴R⁵, —NH(CH₂)_(n)NR⁴R⁵, —(CH₂)_(n)OR⁶,—(CH₂)_(n)NR⁴R⁵, —(CH₂)_(n)C(O)NR⁴R⁵, —(CH₂)_(n)N(R⁴)C(O)R⁶,—(CH₂)_(n)S(O)₂NR⁴R⁵, (CH₂)_(n)N(R⁴)S(O)₂R⁶, -ZAr, —(CH₂)_(n)S(O)₂R⁶,—(OCH₂)_(n)S(O)₂R⁶, —N(R⁴)S(O)₂R⁶, —N(R⁴)C(O)R⁶, —(CH₂)_(n)N(R⁴)S(O)₂R⁶,—(CH₂)_(n)N(R⁴)C(O)R⁶ or —(CH₂)_(n)C(O)alkyl; R³ is selected from alkyl,alkoxy, —CF₃, halo, —O(CH₂)_(n)OR⁶, —O(CH₂)_(n)NR⁴R⁵, phenyl, -Ophenyl,—NHphenyl, —N(alkyl)phenyl, —Oheteroaryl, —NHheteroaryl,—N(alkyl)heteroaryl, cyclohexyl, benzo[1,3]dioxolyl, morpholinyl,pyridyl, pyrimidinyl, pyrazinyl, piperazinyl, piperidinyl, pyridizinyl,thienyl, furyl, pyrazolyl, pyrrolyl, triazolyl, indanyl, imidazolyl,oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl orthiadiazolyl; wherein said alkyl, alkoxy, phenyl, cyclohexyl,benzo[1,3]dioxolyl, morpholinyl, pyridyl, pyrimidinyl, pyrazinyl,piperazinyl, piperidinyl, pyridizinyl, thienyl, furyl, pyrazolyl,pyrrolyl, triazolyl, indanyl, imidazolyl, oxazolyl, thiazolyl,oxediazolyl, isothiazolyl, isoxazolyl and thiadiazolyl groups may beoptionally substituted by one or more groups, which may be the same ordifferent, selected from R²; R⁴ and R⁵ may be the same or different andrepresent —H or alkyl or R⁴ and R⁵ together with the nitrogen atom towhich they are attached form a heterocyclic ring; R⁶ is —H, alkyl oraryl; R⁷ is —H, alkyl or aryl; R⁸ is selected from H, alkyl,hydroxyalkyl, cycloalkyl, aralkyl, alkoxyalkyl, cycloalkylalkyl,heterocyclylalkyl, —S(O)_(m)R⁶, —C(O)CF₃, —C(O)alkyl, —C(O)cycloalkyl,—C(O)aralkyl, —C(O)Ar, —C(O)(CH₂)_(n)OR⁶, —C(O)(CH₂)_(n)NR⁴R⁵,C(O)alkoxy, —C(O)NR⁴R⁵, —(CH₂)_(n)C(O)alkoxy, —(CH₂)_(n)OC(O)R⁶,—(CH₂)_(n)OR⁶, —(CH₂)_(n)NR⁴R⁵, —(CH₂)_(n)C(O)NR⁴R⁵,—(CH₂)_(n)N(R⁴)C(O)R⁶, —(CH₂)_(n)S(O)₂NR⁴R⁵, —(CH₂)_(n)N(R⁴)S(O)₂R⁶,—(CH₂)_(n)S(O)₂R⁶, —(CH₂)_(n)N(R⁴)S(O)₂R⁶, —(CH₂)_(n)N(R⁴)C(O)R⁶ or—(CH₂)_(n)C(O)alkyl; or where X is NR⁸ and Y is C(R⁹)₂, R⁸ may combinewith R¹ to form a benzoquinuclidine group; R⁹ is H or R¹; Ar is aryl orheteroaryl, each of which may be optionally substituted by R²; Z is abond, O, S, NR⁷ or CH₂; m is 0, 1 or 2; n is an integer value from 1 to6; q and r are independently selected from 0, 1, 2 or 3; s is 0, 1, 2 or3; and X and Y are selected from the following combinations: X Y N CR⁹NR⁸ C(R⁹)₂ CR⁹ N C(R⁹)₂ NR⁸

with the proviso that said compound of formula (I) is not a compoundselected from:N-{3-[(N,N-Dimethylamino)methyl]-1,2,3,4-tetrahydro-7-guinolinyl}-4biphenylcarboxamide;N-{3-[(N,N-Dimethylamino)methyl]-1-formyl-1,2,3,4-tetrahydro-7-quinolinyl}-4-biphenylcarboxamide;N-{1-Acetyl-3-[(N,N-dimethylamino)methyl]-1,2,3,4-tetrahydro-7-quinolinyl}-4biphenylcarboxamide;N-{3-[(N,N-Dimethylamino)methyl]-1-methylsulfonyl-1,2,3,4-tetrahydro-7quinolinyl}-4-biphenylcarboxamide;5-amino-N-isoquinolin-5-yl-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3carboxamide;5-methyl-N-quinolin-8-yl-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3carboxamide;5-methyl-N-quinolin-7-yl-1-[3-trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide;5-methyl-N-quinolin-3-yl-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide;N-isoquinolin-5-yl-5-methyl-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide;5-methyl-N-quinolin-5-yl-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide;1-(3-chlorophenyl)-N-isoquinolin-5-yl-5-methyl-1H-pyrazole-3-carboxamide;N-isoquinolin-5-yl-1-(3-methoxyphenyl)-5-methyl-1H-pyrazole-3-carboxamide;1-(3-fluorophenyl)-N-isoquinolin-5-yl-5-methyl-1H-pyrazole-3-carboxamide;1-(2-chloro-5-trifluoromethylphenyl)-N-isoquinolin-5-yl-5-methyl-1H-pyrazole-3carboxamide;5-methyl-N-(3-methylisoquinolin-5-yl)-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide;and5-methyl-N-(1,2,3,4-tetrahydroisoquinolin-5-yl)-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide.9. A compound according to claim 8 selected from the group of:1-(1-methylethyl)-N-(7-quinolinyl)-2-(trifluoromethyl)-1H-benzimidazole-5-carboxamide;1-(phenylmethyl)-N-(7-quinolinyl)-1H-indole-3-carboxamide;1-methyl-N-(7-quinolinyl)-1H-indole-3-carboxamide;2′-(((2-(dimethylamino)ethyl)oxy)methyl)-N-(7-quinolinyl)-1,1′-biphenyl-4-carboxamide;2′-(((3-(1-pyrrolidinyl)propyl)amino)methyl)-N-(7-quinolinyl)-1,1′-biphenyl-4-carboxamide;2-(1-methylethyl)-N-(7-quinolinyl)-1,2,3,4-tetrahydro-6-isoquinolinecarboxamide;2-(1-phenylethyl)-N-(7-quinolinyl)-1,2,3,4-tetrahydro-6-isoquinolinecarboxamide;2′-(hydroxymethyl)-N-(7-quinolinyl)-1,1′-biphenyl-4-carboxamide;2-(phenylmethyl)-N-(7-quinolinyl)-1,2,3,4-tetrahydro-6-isoquinolinecarboxamide;2,2-dimethyl-N-(7-quinolinyl)-3,4-dihydro-2H-chromene-6-carboxamide;2′-formyl-N-(7-quinolinyl)-1,1′-biphenyl-4-carboxamide;3-(2-furanyl)-N-(7-quinolinyl)-6-(trifluoromethyl)thieno[3,2-b]pyridine-2-carboxamide;3-(3-pyridinyl)-N-(7-quinolinyl)-6-(trifluoromethyl)thieno[3,2-b]pyridine-2-carboxamide;3-bromo-1-(2-(dimethylamino)ethyl)-N-(7-quinolinyl)-1H-indole-6-carboxamide;3-bromo-1-(phenylmethyl)-N-(7-quinolinyl)-1H-indole-6-carboxamide;3-bromo-1-methyl-N-(7-quinolinyl)-1H-indole-6-carboxamide;3-bromo-N-(7-quinolinyl)-1H-indole-6-carboxamide;4-((2-(methyloxy)phenyl)oxy)-N-(7-quinolinyl)benzamide;4-((2-chlorophenyl)oxy)-N-(7-quinolinyl)benzamide;4-((4-fluorophenyl)oxy)-N-(7-quinolinyl)benzamide;4-(phenyloxy)-N-(7-quinolinyl)benzamide;4-bromo-N-(7-quinolinyl)benzamide;5-bromo-1-(phenylmethyl)-N-(7-quinolinyl)-1H-indole-2-carboxamide;5-bromo-1-methyl-N-(7-quinolinyl)-1H-indole-2-carboxamide;6-(3-pyridinyl)-N-(7-quinolinyl)-2-naphthalenecarboxamide;6-(4-(1-methylethyl)-1-piperazinyl)-N-(7-quinolinyl)-2-naphthalenecarboxamide;6-(4-morpholinyl)-N-(7-quinolinyl)-2-naphthalenecarboxamide;6-bromo-1-(phenylmethyl)-N-(7-quinolinyl)-1H-indole-2-carboxamide;6-bromo-1-methyl-N-(7-quinolinyl)-1H-indole-2-carboxamide;6-bromo-N-(3-(hydroxymethyl)-1,2,3,4-tetrahydro-7-quinolinyl)-2-naphthalenecarboxamide;6-bromo-N-(3-(hydroxymethyl)-2-oxo-1,2,3,4-tetrahydro-7-quinolinyl)-2-naphthalenecarboxamide;6-bromo-N-(7-quinolinyl)-1H-indole-2-carboxamide;6-bromo-N-(7-quinolinyl)-2-naphthalenecarboxamide;6-bromo-N-(7-quinolinyl)-2-quinolinecarboxamide;N-(3-(hydroxymethyl)-2-oxo-1,2,3,4-tetrahydro-7-quinolinyl)-2,2-dimethyl-3,4-dihydro-2H-chromene-6-carboxamide;N-(7-quinolinyl)-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydro-6-isoquinolinecarboxamide;N-(7-quinolinyl)-2-(3-(trifluoromethyl)-2-pyridinyl)-1,2,3,4-tetrahydro-6-isoquinolinecarboxamide;N-(7-quinolinyl)-2-naphthalenecarboxamide;N-(7-quinolinyl)-4-((4-(trifluoromethyl)phenyl)oxy)benzamide;N-(7-quinolinyl)-4-(3-(trifluoromethyl)-2-pyridinyl)benzamide;N-(7-quinolinyl)-5-(trifluoromethyl)-1-benzothiophene-2-carboxamide;N-(7-quinolinyl)-6-(trifluoromethyl)-1-benzothiophene-2-carboxamide;N-(7-quinolinyl)-6-(trifluoromethyl)-1H-benzimidazole-2-carboxamide;N-(7-quinolinyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxamide;andN-(7-quinolinyl)-6-(trifluoromethyl)thieno[3,2-b]pyridine-2-carboxamide;or any pharmaceutically-acceptable salts or hydrates thereof.
 10. Amethod of treating acute, inflammatory and neuropathic pain, dentalpain, general headache, migraine, cluster headache, mixed-vascular andnon-vascular syndromes, tension headache, general inflammation,arthritis, rheumatic diseases, osteoarthritis, inflammatory boweldisorders, inflammatory eye disorders, inflammatory or unstable bladderdisorders, psoriasis, skin complaints with inflammatory components,chronic inflammatory conditions, inflammatory pain and associatedhyperalgesia and allodynia, neuropathic pain and associated hyperalgesiaand allodynia, diabetic neuropathy pain, causalgia, sympatheticallymaintained pain, deafferentation syndromes, asthma, epithelial tissuedamage or dysfunction, herpes simplex, disturbances of visceral motilityat respiratory, genitourinary, gastrointestinal or vascular regions,wounds, burns, allergic skin reactions, pruritus, vitiligo, generalgastrointestinal disorders, gastric ulceration, duodenal ulcers,diarrhea, gastric lesions induced by necrotising agents, hair growth,vasomotor or allergic rhinitis, bronchial disorders or bladderdisorders, comprising the step of administering a compound according toclaim 1.